U.S. patent application number 13/181978 was filed with the patent office on 2012-01-19 for synthesis and anticancer activity of aryl and heteroaryl-quinolin derivatives.
This patent application is currently assigned to Efficient Pharma Management Corporate. Invention is credited to Li-Chen Chou, Jing-Gung Chung, Chi-Hung Huang, Li-Jiau Huang, Sheng-Chu Kuo, Kuo-Hsiung Lee, Meng-Tung Tsai, Tzong-Der Way, Tian-Shung Wu, Jai-Sing Yang.
Application Number | 20120015908 13/181978 |
Document ID | / |
Family ID | 44533096 |
Filed Date | 2012-01-19 |
United States Patent
Application |
20120015908 |
Kind Code |
A1 |
Kuo; Sheng-Chu ; et
al. |
January 19, 2012 |
SYNTHESIS AND ANTICANCER ACTIVITY OF ARYL AND HETEROARYL-QUINOLIN
DERIVATIVES
Abstract
A compound of Formula I is disclosed as follows: ##STR00001## or
a pharmaceutically acceptable salt, prodrug, solvate, or metabolite
thereof, wherein R is hydrogen, P(.dbd.O)(OH).sub.2,
P(.dbd.O)(O(C.sub.1-C.sub.18)alkylene(C.sub.6-C.sub.20)aryl).sub.2,
P(.dbd.O)(OH)(OM), P(.dbd.O)(OM).sub.2, P.dbd.O(O.sub.2M),
S(.dbd.O)(OH).sub.2,
S(.dbd.O)(O(C.sub.1-C.sub.18)alkylene(C.sub.6-C.sub.20)aryl).sub.2,
S(.dbd.O)(OH)(OM), S(.dbd.O)(OM).sub.2; M is a monovalent or
divalent metal ion, or alkylammonium ion; W is
(C.sub.6-C.sub.20)aryl, (C.sub.6-C.sub.20)heteroaryl,
(C.sub.1-C.sub.18)alkyl(C.sub.6-C.sub.20)aryl,
(C.sub.1-C.sub.18)alkyl(C.sub.6-C.sub.20)heteroaryl,
hydroxy(C.sub.6-C.sub.20)aryl, hydroxy(C.sub.6-C.sub.20)heteroaryl,
(C.sub.1-C.sub.18)alkoxy(C.sub.6-C.sub.20)aryl,
(C.sub.1-C.sub.18)alkoxy(C.sub.6-C.sub.20)heteroaryl,
(C.sub.1-C.sub.18)alkylenedioxy(C.sub.6-C.sub.20)aryl,
(C.sub.1-C.sub.18)alkylenedioxy(C.sub.6-C.sub.20)heteroaryl,
halo(C.sub.6-C.sub.20)aryl, halo(C.sub.6-C.sub.20)heteroaryl,
(C.sub.1-C.sub.18)alkylamino(C.sub.6-C.sub.20)aryl,
(C.sub.1-C.sub.18)alkylamino(C.sub.6-C.sub.20)heteroaryl,
(C.sub.1-C.sub.18)cycloalkylamino(C.sub.6-C.sub.20)aryl, or
(C.sub.1-C.sub.18)cycloalkylamino(C.sub.6-C.sub.20)heteroaryl, and
their OR.sub.8 substutes; R.sub.5 is (C.sub.1-C.sub.18alkoxy,
hydrogen, hydroxyl,
O--(C.sub.1-C.sub.18)alkyl(C.sub.6-C.sub.20)aryl, halo or OR.sub.8,
or R.sub.5 and R.sub.6 are (C.sub.1-C.sub.18)dioxy provided that
R.sub.7 is hydrogen; R.sub.6 is hydroxyl,
O--(C.sub.1-C.sub.18)alkyl(C.sub.6-C.sub.20)aryl, halo or OR.sub.R,
(C.sub.1-C.sub.18)alkoxy, (C.sub.1-C.sub.18)alkylamino, or
(C.sub.1-C.sub.18)cycloalkylamino, or R.sub.6 and R.sub.7 are
(C.sub.1-C.sub.18)dioxy provided that R.sub.5 is hydrogen; R.sub.7
is hydrogen, halo or OR.sub.8, hydroxyl, or
O--(C.sub.1-C.sub.18)alkyl(C.sub.6-C.sub.20)aryl; and R.sub.8 is
P(.dbd.O)(OH).sub.2,
P(.dbd.O)(O(C.sub.1-C.sub.18)alkyl(C.sub.6-C.sub.20)aryl).sub.2,
P(.dbd.O)(OH)(OM), or P(.dbd.O)(OM).sub.2, P.dbd.O(O.sub.2M).
Inventors: |
Kuo; Sheng-Chu; (Taichung
City, TW) ; Lee; Kuo-Hsiung; (Chapel Hill, NC)
; Huang; Li-Jiau; (Taichung City, TW) ; Chou;
Li-Chen; (Taichung City, TW) ; Wu; Tian-Shung;
(Tainan City, TW) ; Way; Tzong-Der; (Taichung
City, TW) ; Chung; Jing-Gung; (Taichung City, TW)
; Yang; Jai-Sing; (Taichung City, TW) ; Huang;
Chi-Hung; (Taoyuan County, TW) ; Tsai; Meng-Tung;
(Taichung City, TW) |
Assignee: |
Efficient Pharma Management
Corporate
Taipei
TW
|
Family ID: |
44533096 |
Appl. No.: |
13/181978 |
Filed: |
July 13, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61364760 |
Jul 15, 2010 |
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Current U.S.
Class: |
514/81 ;
514/235.2; 514/291; 514/312; 514/82; 544/128; 546/153; 546/24;
546/25; 546/90 |
Current CPC
Class: |
C07D 493/04 20130101;
C07F 9/60 20130101; A61P 35/02 20180101; C07F 9/6561 20130101; A61P
35/00 20180101; C07D 401/04 20130101; C07F 9/65583 20130101; C07D
215/22 20130101; C07D 215/38 20130101; C07D 215/233 20130101 |
Class at
Publication: |
514/81 ; 546/153;
514/312; 546/90; 514/291; 546/25; 514/82; 546/24; 544/128;
514/235.2 |
International
Class: |
A61K 31/675 20060101
A61K031/675; A61K 31/47 20060101 A61K031/47; C07D 491/056 20060101
C07D491/056; A61K 31/4741 20060101 A61K031/4741; C07F 9/60 20060101
C07F009/60; A61P 35/00 20060101 A61P035/00; A61K 31/5377 20060101
A61K031/5377; C07D 405/14 20060101 C07D405/14; A61K 31/4709
20060101 A61K031/4709; C07D 413/10 20060101 C07D413/10; C07D 401/10
20060101 C07D401/10; C07D 215/233 20060101 C07D215/233; C07D 413/14
20060101 C07D413/14 |
Claims
1. A compound of Formula I: ##STR00105## or a pharmaceutically
acceptable salt, prodrug, solvate, or metabolite thereof, wherein R
is hydrogen, P(.dbd.O)(OH).sub.2,
P(.dbd.O)(O(C.sub.1-C.sub.18)alkylene(C.sub.6-C.sub.20)aryl).sub.2,
P(.dbd.O)(OH)(OM), P(.dbd.O)(OM).sub.2, P.dbd.O(O.sub.2M),
S(.dbd.O)(OH).sub.2,
S(.dbd.O)(O(C.sub.1-C.sub.18)alkylene(C.sub.6-C.sub.20)aryl).sub.2,
S(.dbd.O)(OH)(OM), S(.dbd.O)(OM).sub.2; M is a monovalent or
divalent metal ion, or alkylammonium ion, W is
(C.sub.6-C.sub.20)aryl, (C.sub.6-C.sub.20)heteroaryl,
(C.sub.1-C.sub.18)alkyl(C.sub.6-C.sub.20)aryl,
(C.sub.1-C.sub.18)alkyl(C.sub.6-C.sub.20)heteroaryl,
hydroxy(C.sub.6-C.sub.20)aryl, hydroxy(C.sub.6-C.sub.20)heteroaryl,
(C.sub.1-C.sub.18)alkoxy(C.sub.6-C.sub.20)aryl,
(C.sub.1-C.sub.18)alkoxy(C.sub.6-C.sub.20)heteroaryl,
(C.sub.1-C.sub.18)alkylenedioxy(C.sub.6-C.sub.20)aryl,
(C.sub.1-C.sub.18)alkylenedioxy(C.sub.6-C.sub.20)heteroaryl,
halo(C.sub.6-C.sub.20)aryl, halo(C.sub.6-C.sub.20)heteroaryl,
(C.sub.1-C.sub.18)alkylamino(C.sub.6-C.sub.20)aryl,
(C.sub.1-C.sub.18)alkylamino(C.sub.6-C.sub.20)heteroaryl,
(C.sub.1-C.sub.18)cycloalkylamino(C.sub.6-C.sub.20)aryl, or
(C.sub.1-C.sub.18)cycloalkylamino(C.sub.6-C.sub.20)heteroaryl, and
their OR.sub.8 substutes; R.sub.5 is (C.sub.1-C.sub.18)alkoxy,
hydrogen, hydroxyl,
O--(C.sub.1-C.sub.18)alkyl(C.sub.6-C.sub.20)aryl, halo or OR.sub.8,
or R.sub.5 and R.sub.6 are (C.sub.1-C.sub.18)dioxy provided that
R.sub.7 is hydrogen; R.sub.6 is hydroxyl,
O--(C.sub.1-C.sub.18)alkyl(C.sub.6-C.sub.20)aryl, halo, OR.sub.8,
(C.sub.1-C.sub.18)alkoxy, (C.sub.1-C.sub.18)alkylamino, or
(C.sub.1-C.sub.18)cycloalkylamino, or R.sub.6 and R.sub.7 are
(C.sub.1-C.sub.18)dioxy provided that R.sub.5 is hydrogen; R.sub.7
is hydrogen, hydroxyl, halo or OR.sub.8, or
O--(C.sub.1-C.sub.18)alkyl(C.sub.6-C.sub.20)aryl; and R.sub.8 is
P(.dbd.O)(OH).sub.2,
P(.dbd.O)(O(C.sub.1-C.sub.18)alkyl(C.sub.6-C.sub.20)aryl).sub.2,
P(.dbd.O)(OH)(OM), or P(.dbd.O)(OM).sub.2. P.dbd.O(O.sub.2M); M is
a monovalent or divalent (ex: Mg, Ca) metal ion, alkylammonium ion
(ex: N.sym.R).
2. The compound of claim 1, wherein: R is hydrogen,
P(.dbd.O)(OH)(ONa), or P(.dbd.O)(ONa).sub.2; M is sodium; W is
2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,
benzo[d][1,3]dioxol-4-yl, 2,3-dimethoxyphenyl, 2,5-dimethoxyphenyl,
2-methoxyphenyl, 4-methoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl,
4-hydroxyphenyl, 4-hydroxy-3-methoxyphenyl,
5-hydroxy-2-methoxyphenyl, 2,5-dihydroxyphenyl,
benzo[b]thiophen-3-yl, benzo[b]thiophen-2-yl, benzo[b]furan-3-yl,
naphtha-1-yl, naphtha-2-yl, quinolin-4-yl, quinolin-3-yl,
quinolin-2-yl, quinolin-5-yl, or anthracen-1-yl, and their OR.sub.8
substitutes; R.sub.5 is hydrogen, methoxy, hydroxyl, halo or
OR.sub.8, or R.sub.5 and R.sub.6 are methylenedioxy provided that
R.sub.7 is hydrogen; R.sub.6 is N,N-dimethylamino, hydroxyl, halo
or OR.sub.8, methoxy, N-morpholino, or N-pyrrolindino, or R.sub.6
and R.sub.7 are methylenedioxy provided that R.sub.5 is hydrogen;
R.sub.7 is hydrogen, hydroxyl, halo or OR.sub.8, or O-benzyl; and
R.sub.8 is P(.dbd.O)(OH).sub.2, P(.dbd.O)(O-benzyl).sub.2,
P(.dbd.O)(OH)(ONa), or P(.dbd.O)(ONa).sub.2.
3. The compound of claim 2, wherein: R is hydrogen; W is
2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl; R.sub.5 is
hydrogen, methoxy, hydroxyl, or OR.sub.8; R.sub.6 is hydroxyl or
methoxy; R.sub.7 is hydrogen, hydroxyl, or O-benzyl; and R.sub.8 is
hydrogen.
4. The compound of claim 2, wherein: R is hydrogen; W is
benzo[d][1,3]dioxol-4-yl, 2,3-dimethoxyphenyl, 2,5-dimethoxyphenyl,
2-methoxyphenyl, 4-methoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl,
4-hydroxyphenyl, 4-hydroxy-3-methoxyphenyl,
5-hydroxy-2-methoxyphenyl, or 2,5-dihydroxyphenyl; R.sub.5 is
hydrogen, methoxy, hydroxyl, or OR.sub.8; R.sub.6 is hydroxyl or
methoxy; R.sub.7 is hydrogen, hydroxyl, or O-benzyl; and R.sub.8 is
hydrogen.
5. The compound of claim 2, wherein: R is hydrogen; W is
2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl; R.sub.5 and R.sub.6
are methylenedioxy provided that R.sub.7 is hydrogen; and R.sub.8
is hydrogen.
6. The compound of claim 2, wherein: R is hydrogen; W is
benzo[b]thiophen-3-yl, benzo[b]thiophen-2-yl, benzo[b]furan-3-yl,
naphtha-1-yl, naphtha-2-yl, quinolin-4-yl, quinolin-3-yl,
quinolin-2-yl, quinolin-5-yl, or anthracen-1-yl; and R.sub.6 and
R.sub.7 are methylenedioxy provided that R.sub.5 is hydrogen.
7. The compound of claim 2, wherein: R is hydrogen,
P(.dbd.O)(OH).sub.2. P(.dbd.O)(O-benzyl).sub.2, W is naphthalene,
dibenzyl-3-phenyl phosphate, 3-phenyl dihydrogen phosphate,
3-([bis-[(benzyl)oxy]]phosphorypoxy-5-methoxyphenyl,
3-(dihydrogen)phosphate-5-methoxyphenyl; and R.sub.4 and R.sub.7
are methylenedioxy provided that R.sub.5 is hydrogen.
8. The compound of claim 1, wherein the compound is
2-(2-Fluorophenyl)-5,6-dimethoxyquinolin-4-one;
2-(3-Fluorophenyl)-5,6-dimethoxyquinolin-4-one;
2-(4-Fluorophenyl)-5,6-dimethoxyquinolin-4-one;
2-(2-Fluorophenyl)-5,6-methylenedioxyquinolin-4-one;
2-(3-Fluorophenyl)-5,6-methylenedioxyquinolin-4-one;
2-(4-Fluorophenyl)-5,6-methylenedioxyquinolin-4-one;
2-(2-Fluorophenyl)-5-hydroxy-6-methoxyquinolin-4-one;
2-(3-Fluorophenyl)-5-hydroxy-6-methoxyquinolin-4-one;
2-(4-Fluorophenyl)-5-hydroxy-6-methoxyquinolin-4-one;
2-(2-Fluorophenyl)-5,6-dihydroxyquinolin-4-one;
2-(3-Fluorophenyl)-5,6-dihydroxyquinolin-4-one;
2-(4-Fluorophenyl)-5,6-dihydroxyquinolin-4-one;
2-(2-Fluorophenyl)-7-hydroxy-6-methoxyquinolin-4-one;
2-(3-Fluorophenyl)-7-hydroxy-6-methoxyquinolin-4-one;
2-(4-Fluorophenyl)-7-hydroxy-6-methoxyquinolin-4-one;
7-Benzyloxy-2-(2-fluorophenyl)-6-methoxyquinolin-4-one;
7-Benzyloxy-2-(3-fluorophenyl)-6-methoxyquinolin-4-one;
7-Benzyloxy-2-(4-fluorophenyl)-6-methoxyquinolin-4-one; sodium
2-(3-fluorophenyl)-6-methoxy-4-oxo-1,4-dihydroquinolin-5-yl
phosphate;
2-(benzo[d][1,3]dioxol-4-yl)-6-pyrrolidinoquinolin-4-one;
2-(2,3-dimethoxyphenyl)-6-morpholinoquinolin-4-one;
2-(2,3-dimethoxyphenyl)-6-pyrrolidinoquinolin-4-one;
2-(2,5-dimethoxyphenyl)-6-morpholinoquinolin-4-one;
2-(2,5-dimethoxyphenyl)-6-pyrrolidinoquinolin-4-one;
2-(2-methoxyphenyl)-6-morpholinoquinolin-4-one;
2-(2,5-dimethoxyphenyl)-6-pyrrolidinoquinolin-4-one;
2-(4-methoxyphenyl)-6-morpholinoquinolin-4-one;
2-(4-methoxyphenyl)-6-pyrrolidinoquinolin-4-one;
2-(2-Hydroxyphenyl)-6-morpholinoquinolin-4-one;
2-(2-hydroxyphenyl)-6-pyrrolidinoquinolin-4-one;
2-(2-hydroxyphenyl)-6-dimethylaminoquinolin-4-one;
2-(3-Hydroxyphenyl)-6-morpholinoquinolin-4-one;
2-(3-hydroxyphenyl)-6-pyrrolidinoquinolin-4-one;
2-(3-hydroxyphenyl)-6-dimethylaminoquinolin-4-one;
2-(4-Hydroxyphenyl)-6-morpholinoquinolin-4-one;
2-(4-hydroxyphenyl)-6-pyrrolidinoquinolin-4-one;
2-(4-hydroxyphenyl)-6-dimethylaminoquinolin-4-one:
2-(4-hydroxy-3-methoxyphenyl)-6-morpholinoquinolin-4-one;
2-(4-hydroxy-3-methoxyphenyl)-6-pyrrolidinoquinolin-4-one;
2-(5-hydroxy-2-methoxyphenyl)-6-morpholinoquinolin-4-one;
2-(5-hydroxy-2-methoxyphenyl)-6-pyrrolidinoquinolin-4-one;
2-(2,5-dihydroxy-phenyl)-6-morpholinoquinolin-4-one;
2-(2,5-dihydroxy-phenyl)-6-pyrrolidinoquinolin-4-one;
2-(3-Benzo[b]thienyl)-6,7-methylenedioxyquinolin-4-one;
2-(2-Benzo[b]thienyl)-6,7-methylenedioxyquinolin-4-one;
2-(3-Benzo[b]furyl)-6,7-methylenedioxyquinolin-4-one;
2-(2-Benzo[h]furyl)-6,7-methylenedioxyquinolin-4-one;
2-(1-Naphthalenyl)-6,7-methylenedioxyquinolin-4-one;
2-(2-Naphthalenyl)-6,7-methylenedioxyquinolin-4-one;
2-(4-Quinolinyl)-6,7-methylenedioxyquinolin-4-one;
2-(3-Quinolinyl)-6,7-methylenedioxyquinolin-4-one;
2-(2-Quinolinyl)-6,7-methylenedioxyquinolin-4-one;
2-(5-Quinolinyl)-6,7-methylenedioxyquinolin-4-one;
2-(1-Anthracenyl)-6,7-methylenedioxyquinolin-4-one; Dibenzyl
2-(1-naphthalenyl)-6,7-methylenedioxyquinolin-4-yl Phosphate;
2-(1-Naphthalenyl)-6,7-methylenedioxyquinolin-4-yl Dihydrogen
Phosphate; Dibenzyl
2-(3-benzo[b]furyl)-6,7-methylenedioxyquinolin-4-yl Phosphate;
2-(3-Benzo[b]furyl)-6,7-methylenedioxyquinolin-4-yl Dihydrogen
Phosphate; Dibenzyl
3-(4-oxo-6-(pyrrolidin-1-yl)-1,4-dihydroquinolin-2-yl)phenyl
phosphate;
3-(4-Oxo-6-(pyrrolidin-1-yl)-1,4-dihydroquinolin-2-yl)phenyl
dihydrogen phosphate; Dibenzyl
2-(3-([bis-([benzyl)oxy]]phosphoryl)oxy-5-methoxyphenyl)-6,7-methylenedio-
xyquinolin-4-yl phosphate;
2-(3-([bis-[(benzyl)oxy]]phosphoryl)oxy-5-methoxyphenyl)-6,7-methylenedio-
xyquinolin-4-one;
2-(3-(dihydrogen)phosphate-5-methoxyphenyl)-6,7-methylenedioxyquinolin-4--
one, or a pharmaceutically acceptable salt, prodrug, solvate, or
metabolite thereof.
9. The compound of claim 1, wherein the compound is selected from
the group consisting of ##STR00106## ##STR00107## ##STR00108##
wherein R=H, or a pharmaceutically acceptable salt, prodrug,
solvate, or metabolite thereof.
10. The compound of claim 1, wherein the compound is selected from
the group consisting of ##STR00109## or a pharmaceutically
acceptable salt, prodrug, solvate, or metabolite thereof.
11. The compound of claim 1, wherein the compound is selected from
the group consisting of ##STR00110## ##STR00111## ##STR00112##
##STR00113## wherein R=H, or a pharmaceutically acceptable salt,
prodrug, solvate, or metabolite thereof.
12. The compound of claim 1, wherein the compound is selected from
the group consisting of ##STR00114## ##STR00115## wherein R=H, or a
pharmaceutically acceptable salt, prodrug, solvate, or metabolite
thereof.
13. The compound of claim 1, wherein the compound is selected from
the group consisting of ##STR00116## ##STR00117##
14. A composition comprising a compound according to claim 1 and a
pharmaceutically acceptable carrier.
15. The compound of claim 1, with the proviso that if R5 is
hydroxyl, then R6 is not (Cl)alkoxy and W is not
3-fluorophenyl.
16. The compound of claim 1, wherein R5 is hydroxyl, R6 is
(Cl)alkoxy and W is 3-fluorophenyl.
17. The compound of claim 1, wherein the compound is
2-(3-Fluorophenyl)-6-methoxy-4-oxo-1,4-dihydroquinolin-5-yl
dihydrogen phosphate, or Sodium
2-(3-fluorophenyl)-6-methoxy-4-oxo-1,4-dihydroquinolin-5-yl
phosphate.
18. A method for treating a tumor disease comprising administering
to a subject in need thereof an effective amount of a composition
according to claim 14.
19. A process for preparing a compound of Formula I ##STR00118##
wherein R is hydrogen; W is 2-fluorophenyl, 3-fluorophenyl,
4-fluorophenyl, benzo[d][1,3]dioxol-4-yl, 2,3-dimethoxyphenyl,
2,5-dimethoxyphenyl, 2-methoxyphenyl, 4-methoxyphenyl,
2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl,
2-benzyloxyphenyl, 3-benzyloxyphenyl, 4-benzyloxyphenyl,
4-benzyloxy-3-methoxyphenyl, 3-benzyloxy-5-methoxyphenyl,
4-hydroxy-3-methoxyphenyl, 5-hydroxy-2-methoxyphenyl,
2,5-dihydroxyphenyl, benzo[b]thiophen-3-yl, benzo[b]thiophen-2-yl,
benzo[b]furan-3-yl, naphtha-1-yl, naphtha-2-yl, quinolin-4-yl,
quinolin-3-yl, quinolin-2-yl, quinolin-5-yl, or anthracen-1-yl;
R.sub.5 is hydrogen, methoxy, hydroxyl, or OR.sub.8, or R.sub.5 and
R.sub.6 are methylenedioxy provided that R.sub.7 is hydrogen;
R.sub.6 is N,N-dimethylamino, hydroxyl, methoxy, N-morpholino, or
N-pyrrolindino, or R.sub.6 and R.sub.7 are methylenedioxy provided
that R.sub.5 is hydrogen; R.sub.7 is hydrogen, hydroxyl, or
O-benzyl; and R.sub.8 is hydrogen; or a pharmaceutically acceptable
salt, prodrug, solvate, or metabolite thereof, comprising: reacting
a compound of Formula II ##STR00119## wherein R.sub.5 is
(C.sub.1-C.sub.18)alkoxy, hydrogen, hydroxyl,
O--(C.sub.1-C.sub.18)alkyl(C.sub.6-C.sub.20)aryl, halo or OR.sub.8
or R.sub.5 and R.sub.6 are (C.sub.1-C.sub.18)dioxy provided that
R.sub.7 is hydrogen; R.sub.6 is hydroxyl,
O--(C.sub.1-C.sub.18)alkyl(C.sub.6-C.sub.20)aryl, halo, OR.sub.8
(C.sub.1-C.sub.18)alkoxy, (C.sub.1-C.sub.18)alkylamino, or
(C.sub.1-C.sub.18)cycloalkylamino or R.sub.6, and R.sub.7 are
(C.sub.1-C.sub.18)dioxy provided that R.sub.5 is hydrogen; R.sub.7
is hydrogen, halo or OR.sub.8 hydroxyl, or
O--(C.sub.1-C.sub.18)alkyl(C.sub.6-C.sub.20)aryl; and R.sub.8 is
hydrogen; with a compound of Formula III ##STR00120## in the
presence of a base; wherein W is 2-fluorophenyl, 3-fluorophenyl,
4-fluorophenyl, benzo[d][1,3]dioxol-4-yl, 2,3-dimethoxyphenyl,
2,5-dimethoxyphenyl, 2-methoxyphenyl, 4-methoxyphenyl,
2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl,
2-benzyloxyphenyl, 3-benzyloxyphenyl, 4-benzyloxyphenyl,
4-benzyloxy-3-methoxyphenyl, 3-benzyloxy-5-methoxyphenyl,
4-hydroxy-3-methoxyphenyl, 5-hydroxy-2-methoxyphenyl,
2,5-dihydroxyphenyl, benzo[b]thiophen-3-yl, benzo[b]thiophen-2-yl,
benzo[b]furan-3-yl, naphtha-1-yl, naphtha-2-yl, quinolin-4-yl,
quinolin-3-yl, quinolin-2-yl, quinolin-5-yl, or anthracen-1-yl to
afford a compound of Formula IV ##STR00121## wherein R is hydrogen;
W is 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,
benzo[d][1,3]dioxol-4-yl, 2,3-dimethoxyphenyl, 2,5-dimethoxyphenyl,
2-methoxyphenyl, 4-methoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl,
4-hydroxyphenyl, 2-benzyloxyphenyl, 3-benzyloxyphenyl,
4-benzyloxyphenyl, 4-benzyloxy-3-methoxyphenyl,
3-benzyloxy-5-methoxyphenyl, 4-hydroxy-3-methoxyphenyl,
5-hydroxy-2-methoxyphenyl, 2,5-dihydroxyphenyl,
benzo[b]thiophen-3-yl, benzo[b]thiophen-2-yl, benzo[b]furan-3-yl,
naphtha-1-yl, naphtha-2-yl, quinolin-4-yl, quinolin-3-yl,
quinolin-2-yl, quinolin-5-yl, or anthracen-1-yl; R.sub.5 is
hydrogen, methoxy, hydroxyl, or OR.sub.8, or R.sub.5 and R.sub.6
are methylenedioxy provided that R.sub.7 is hydrogen; R.sub.6 is
N,N-dimethylamino, hydroxyl, methoxy, N-morpholino, or
N-pyrrolindino, or R.sub.6 and R.sub.7 are methylenedioxy provided
that R.sub.5 is hydrogen; R.sub.7 is hydrogen, hydroxyl, or
O-benzyl; and R.sub.8 is hydrogen; and reacting a compound of
Formula IV with a base to afford the compound of Formula I.
20. The process of claim 19, further comprising dealkylating the
compound of Formula I to afford the compound of Formula I
##STR00122## wherein R is hydrogen; W is 2-fluorophenyl,
3-fluorophenyl, 4-fluorophenyl, benzo[d][1,3]dioxol-4-yl,
2,3-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2-methoxyphenyl,
4-methoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl,
2-benzyloxyphenyl, 3-benzyloxyphenyl, 4-benzyloxyphenyl,
4-benzyloxy-3-methoxyphenyl, 3-benzyloxy-5-methoxyphenyl,
4-hydroxy-3-methoxyphenyl, 5-hydroxy-2-methoxyphenyl,
2,5-dihydroxyphenyl, benzo[b]thiophen-3-yl, benzo[b]thiophen-2-yl,
benzo[b]furan-3-yl, naphtha-1-yl, naphtha-2-yl, quinolin-4-yl,
quinolin-3-yl, quinolin-2-yl, quinolin-5-yl, or anthracen-1-yl;
R.sub.5 is hydrogen, hydroxyl, or methoxy; R.sub.6 is
N,N-dimethylamino, hydroxyl, methoxy, N-morpholino, or
N-pyrrolindino, or R.sub.6 and R.sub.7 are methylenedioxy provided
that R.sub.5 is hydrogen; and R.sub.7 is hydrogen.
Description
REFERENCE TO RELATED APPLICATION
[0001] The present application claims the priority to U.S.
Provisional Application Ser. No. 61/364,760, filed Jul. 15, 2010,
which is herein incorporated by reference in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates generally to derivatives and
analogues of aryl and heteroaryl-quinolin, and more specifically to
synthesis and use of aryl and heteroaryl-quinolin derivatives and
analogues for anticancer activities.
BACKGROUND OF THE INVENTION
[0003] A series of substituted 2-phenylquinolin-4-ones (2-PQs) have
been previously synthesized and identified as new anticancer
agents. Through the process of structure-activity relationship
(SAR) establishment, it was discovered that many of these compounds
had potent cytotoxicity. In a recent in vivo evaluation of a series
of 2-PQs with potent cytotoxicity, excellent antitumor activity was
identified in 2-(2-fluorphenyl)-6,7-methylenedioxyquinolin-4-one
(CHM-2133) and its phosphate derivative (CHM-2133-P) (FIG. 1). See
WO2008/070176A1 and Yu-Hsun Chang et al. (2009) "Design and
Synthesis of 2-(3-Benzo[b]thienyl)-6,7-methylenedioxyquinolin-4-one
Analogues as Potent Antitumor Agents that Inhibit Tubulin Assembly"
J. Med. Chem. 52, 4883-4891, each of which is herein incorporated
by reference in its entirety. There is still a need for discovery
of more potential anticancer compounds.
SUMMARY OF THE INVENTION
[0004] In one aspect, the invention relates to a compound of
Formula I:
##STR00002##
[0005] or a pharmaceutically acceptable salt, prodrug, solvate, or
metabolite thereof, wherein
[0006] R is hydrogen, P(.dbd.O)(OH).sub.2,
P(.dbd.O)(O(C.sub.1-C.sub.18)alkylene(C.sub.6-C.sub.20)aryl).sub.2,
P(.dbd.O)(OH)(OM), P(.dbd.O)(OM).sub.2, P.dbd.O(O.sub.2M),
S(.dbd.O)(OH).sub.2,
S(.dbd.O)(O(C.sub.1-C.sub.18)alkylene(C.sub.6-C.sub.20)aryl).sub.2,
S(.dbd.O)(OH)(OM), S(.dbd.O)(OM).sub.2;
[0007] M is a monovalent and divalent (ex: Mg, Ca) metal ion, or
alkylammonium ion (ex: N.sup..circle-w/dot.R);
[0008] W is (C.sub.6-C.sub.20)aryl, (C.sub.6-C.sub.20)heteroaryl,
(C.sub.1-C.sub.18)alkyl(C.sub.6-C.sub.20)aryl,
(C.sub.1-C.sub.18)alkyl(C.sub.6-C.sub.20)heteroaryl,
hydroxy(C.sub.6-C.sub.20)aryl, hydroxy(C.sub.6-C.sub.20)heteroaryl,
(C.sub.1-C.sub.18)alkoxy(C.sub.6-C.sub.20)aryl,
(C.sub.1-C.sub.18)alkoxy(C.sub.6-C.sub.20)heteroaryl,
(C.sub.1-C.sub.18)alkylenedioxy(C.sub.6-C.sub.20)aryl,
(C.sub.1-C.sub.18)alkylenedioxy(C.sub.6-C.sub.20)heteroaryl,
halo(C.sub.6-C.sub.20)aryl, halo(C.sub.6-C.sub.20)heteroaryl,
(C.sub.1-C.sub.18)alkylamino(C.sub.6-C.sub.20)aryl,
(C.sub.1-C.sub.18)alkylamino(C.sub.6-C.sub.20)heteroaryl,
(C.sub.1-C.sub.18)cycloalkylamino(C.sub.6-C.sub.20)aryl, or
(C.sub.1-C.sub.18)cycloalkylamino(C.sub.6-C.sub.20)heteroaryl, and
their OR.sub.8 substutes;
[0009] R.sub.5 is (C.sub.1-C.sub.18)alkoxy, hydrogen, hydroxyl,
O--(C.sub.1-C.sub.18)alkyl(C.sub.6-C.sub.20)aryl, halo or OR.sub.8,
or R.sub.5 and R.sub.6 are (C.sub.1-C.sub.18)dioxy provided that
R.sub.7 is hydrogen;
[0010] R.sub.6 is hydroxyl,
O--(C.sub.1-C.sub.18)alkyl(C.sub.6-C.sub.20)aryl, halo, OR.sub.8,
(C.sub.1-C.sub.18)alkoxy, (C.sub.1-C.sub.18)alkylamino, or
(C.sub.1-C.sub.18)cycloalkylamino, or R.sub.6 and R.sub.7 are
(C.sub.1-C.sub.18)dioxy provided that R.sub.5 is hydrogen;
[0011] R.sub.7 is hydrogen, halo or OR.sub.8, hydroxyl, or
O--(C.sub.1-C.sub.18)alkyl(C.sub.6-C.sub.20)aryl; and
[0012] R.sub.8 is P(.dbd.O)(OH).sub.2,
P(.dbd.O)(O(C.sub.1-C.sub.18)alkyl(C.sub.6-C.sub.20)aryl).sub.2,
P(.dbd.O)(OH)(OM), or P(.dbd.O)(OM).sub.2, P.dbd.O(O.sub.2M).
[0013] In one embodiment of the invention, the aforementioned class
of the compound is restricted with the proviso that if R5 is
hydroxyl, then R6 is not (Cl)alkoxy and W is not
3-fluorophenyl.
[0014] In another embodiment of the invention, R5 is hydroxyl, R6
is (Cl)alkoxy and W is 3-fluorophenyl.
[0015] In another aspect, the invention relates to a composition
comprising a compound as aforementioned and a pharmaceutically
acceptable carrier.
[0016] Further in another aspect, the invention relates to a method
for treating a tumor disease comprising administering to a subject
in need thereof an effective amount of a composition as
aforementioned. The administering step may be performed in vivo or
in vitro. In one embodiment, the subject is a mammal.
[0017] Yet in another aspect, the invention relates to a process
for preparing a compound as aforementioned comprising reacting a
compound of Formula II
##STR00003##
[0018] wherein R.sub.5 is (C.sub.1-C.sub.18)alkoxy, hydrogen,
hydroxyl, O--(C.sub.1-C.sub.18)alkyl(C.sub.6-C.sub.20)aryl, or
OR.sub.8 or R.sub.5 and R.sub.6 are (C.sub.1-C.sub.18)dioxy
provided that R.sub.7 is hydrogen;
[0019] R.sub.6 is hydroxyl, (C.sub.1-C.sub.18)alkoxy,
O--(C.sub.1-C.sub.18)alkyl(C.sub.6-C.sub.20)aryl,
(C.sub.1-C.sub.18)alkylamino, or (C.sub.1-C.sub.18)cycloalkylamino
or R.sub.6 and R.sub.7 are (C.sub.1-C.sub.18)dioxy provided that
R.sub.5 is hydrogen;
[0020] R.sub.7 is hydrogen, hydroxyl, or
O--(C.sub.1-C.sub.18)alkyl(C.sub.6-C.sub.20)aryl; and
[0021] R.sub.8 is hydrogen; with a compound of Formula III
##STR00004##
[0022] in the presence of a base; wherein W is 2-fluorophenyl,
3-fluorophenyl, 4-fluorophenyl, benzo[d][1,3]dioxol-4-yl,
2,3-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2-methoxyphenyl,
4-methoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl,
2-benzyloxyphenyl, 3-benzyloxyphenyl, 4-benzyloxyphenyl,
4-benzyloxy-3-methoxyphenyl, 3-benzyloxy-5-methoxyphenyl,
4-hydroxy-3-methoxyphenyl, 5-hydroxy-2-methoxyphenyl,
2,5-dihydroxyphenyl, benzo[b]thiophen-3-yl, benzo[b]thiophen-2-yl,
benzo[b]furan-3-yl, naphtha-1-yl, naphtha-2-yl, quinolin-4-yl,
quinolin-3-yl, quinolin-2-yl, quinolin-5-yl, or anthracen-1-yl to
afford a compound of Formula IV
##STR00005##
wherein
[0023] R is hydrogen;
[0024] W is 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl,
benzo[d][1,3]dioxol-4-yl, 2,3-dimethoxyphenyl, 2,5-dimethoxyphenyl,
2-methoxyphenyl, 4-methoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl,
4-hydroxyphenyl, 2-benzyloxyphenyl, 3-benzyloxyphenyl,
4-benzyloxyphenyl, 4-benzyloxy-3-methoxyphenyl,
3-benzyloxy-5-methoxyphenyl, 4-hydroxy-3-methoxyphenyl,
5-hydroxy-2-methoxyphenyl, 2,5-dihydroxyphenyl,
benzo[b]thiophen-3-yl, benzo[b]thiophen-2-yl, benzo[b]furan-3-yl,
naphtha-1-yl, naphtha-2-yl, quinolin-4-yl, quinolin-3-yl,
quinolin-2-yl, quinolin-5-yl, or anthracen-1-yl;
[0025] R.sub.5 is hydrogen, methoxy, hydroxyl, O-benzyl or
OR.sub.8, or R.sub.5 and R.sub.6 are methylenedioxy provided that
R.sub.7 is hydrogen;
[0026] R.sub.6 is N,N-dimethylamino, hydroxyl, O-benzyl, methoxy,
N-morpholino, or N-pyrrolindino, or R.sub.6 and R.sub.7 are
methylenedioxy provided that R.sub.5 is hydrogen;
[0027] R.sub.7 is hydrogen, hydroxyl, or O-benzyl; and
[0028] R.sub.8 is hydrogen; and
[0029] reacting a compound of Formula IV with a base to afford the
compound of Formula I.
[0030] The process may further comprise dealkylating the compound
of Formula I. The dealkylated or non-dealkylated compound of
Formula I may further react with tetrabenzylpyrophosphate (Method
A) or dibenzylphosphite (Method B) to afford the compound of
Formula I, wherein R is P(.dbd.O)(OCH.sub.2Ph).sub.2, which treated
with alcohol provided monophosphate. The monophosphoric acid were
obtained by catalytic hydrogenation of the monophosphate. The
monophosphoric acid may further react with a metal carbonate to
afford the compound of Formula I, wherein R is P(.dbd.O)(OH)(OM),
or P(.dbd.O)(OM).sub.2, in which M is a monovalent metal ion.
[0031] These and other aspects will become apparent from the
following description of the preferred embodiment taken in
conjunction with the following drawings, although variations and
modifications therein may be affected without departing from the
spirit and scope of the novel concepts of the disclosure.
[0032] The accompanying drawings illustrate one or more embodiments
of the invention and, together with the written description, serve
to explain the principles of the invention. Wherever possible, the
same reference numbers are used throughout the drawings to refer to
the same or like elements of an embodiment.
BRIEF DESCRIPTION OF THE DRAWINGS
[0033] FIG. 1 shows the structures of substituted
2-phenylquinolin-4-ones (2-PQs), CHM-2133 and CHM-2133-P--Na.
[0034] FIG. 2 shows the structures of target compounds 16-21 and
37-45.
[0035] FIGS. 3A-3C show differential activity patterns for compound
3b against 60 human cancer cell lines. MG-MID: mean of log X values
(X=GI.sub.50, TGI, and LC.sub.50). Delta: logarithm of the
difference between the MG-MID and the log X of the most sensitive
cell line. Range: logarithm of the difference between the log X of
the most resistant cell line and the log X of the most sensitive
cell line.
[0036] FIGS. 4A-4F show (A) Mean tumor volume-time profiles, (B)
Mean tumor weight-time profiles and (C) Mean body weight-time
profiles in Hep3B xenograft nude mice (n=11) following iv dosing of
doxorubicin at 5 mg/kg (qd) and compound 49 at 7.5, 15, and 30
mg/kg (bid) five days per week for four consecutive weeks; (D) Mean
tumor volume-time profiles, (E) Mean tumor weight-time profiles and
(F) Mean body weight-time profiles in Hep3B xenograft nude mice
(n=11) following oral dosing of doxorubicinat 10 mg/kg (qd) and
compound 49 at 7.5, 15, and 30 mg/kg (bid) five days per week for
four consecutive weeks.
[0037] FIGS. 5A-5F show (A) Mean tumor volume-time profiles (B)
Mean tumor weight-time profiles (C) Mean body weight-time profiles
in Hep3B xenograft nude mice (n=11) following oral dosing of
doxonibicin at 5 mg/kg (qd) and 52 at 7.5, 15, and 30 mg/kg (qd)
five days per week for four consecutive weeks; (D) Mean tumor
volume-time profiles (E) Mean tumor weight-time profiles (F) Mean
body weight-time profiles in Hep3B xenograft nude mice (n=11)
following intravenous dosing of doxorubicin at 10 mg/kg (qd) and 52
at 7.5, 15, and 30 mg/kg (qd) five days per week for four
consecutive weeks.
[0038] FIGS. 6A-6C show (A) Mean tumor volume-time profiles (B)
Mean tumor weight-time profiles (C) Mean body weight-time profiles
in Hep3B xenograft nude mice (n=6) following po dosing of
doxorubicin at 10 mg/kg and 147 at 7.5, 15, and 30 mg/kg five days
per week for four consecutive weeks.
[0039] FIGS. 7A-7C show (A) Mean tumor volume-time profiles (B)
Mean tumor weight-time profiles (C) Mean body weight-time profiles
in Hep3B xenograft nude mice (n=6) following iv dosing of
doxorubicin at 10 mg/kg and 147 at 7.5, 15, and 30 mg/kg five days
per week for four consecutive weeks.
DETAILED DESCRIPTION OF THE INVENTION
[0040] One of ordinary skill in the art would readily appreciate
that the pharmaceutical formulations and methods described herein
can be prepared and practiced by applying known procedures in the
pharmaceutical arts. These include, for example, unless otherwise
indicated, conventional techniques of pharmaceutical sciences
including pharmaceutical dosage form design, drug development,
pharmacology, of organic chemistry, and polymer sciences. See
generally, for example, Remington: The Science and Practice of
Pharmacy, 21'' edition, Lippincott, Williams & Wilkins,
(2005).
DEFINITIONS
[0041] The terms used in this specification generally have their
ordinary meanings in the art, within the context of the invention,
and in the specific context where each term is used. Certain terms
that are used to describe the invention are discussed below, or
elsewhere in the specification, to provide additional guidance to
the practitioner regarding the description of the invention. For
convenience, certain terms may be highlighted, for example using
italics and/or quotation marks. The use of highlighting has no
influence on the scope and meaning of a term; the scope and meaning
of a term is the same, in the same context, whether or not it is
highlighted. It will be appreciated that same thing can be said in
more than one way. Consequently, alternative language and synonyms
may be used/for any one or more of the terms discussed herein, nor
is any special significance to be placed upon whether or not a term
is elaborated or discussed herein. Synonyms for certain terms are
provided. A recital of one or more synonyms does not exclude the
use of other synonyms. The use of examples anywhere in this
specification including examples of any terms discussed herein is
illustrative only, and in no way limits the scope and meaning of
the invention or of any exemplified term. Likewise, the invention
is not limited to various embodiments given in this
specification.
[0042] Unless otherwise defined, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention pertains. In the
case of conflict, the present document, including definitions will
control.
[0043] As used herein, "around", "about" or "approximately" shall
generally mean within 20 percent, preferably within 10 percent, and
more preferably within 5 percent of a given value or range.
Numerical quantities given herein are approximate, meaning that the
term "around", "about" or "approximately" can be inferred if not
expressly stated.
[0044] The term "and/or" refers to any one of the items, any
combination of the items, or all of the items with which this term
is associated.
[0045] The singular forms "a," "an," and "the" include plural
reference unless the context clearly dictates otherwise. The claims
may be drafted to exclude any optional element. As such, this
statement is intended to serve as antecedent basis for use of such
exclusive terminology as "solely," "only," and the like in
connection with the recitation of claim elements, or use of a
"negative" limitation.
[0046] Specific and preferred values listed below for radicals,
substituents, and ranges, are for illustration only; they do not
exclude other defined values or other values within defined ranges
for the radicals and substituents.
[0047] The term "administration" refers to a method of placing a
device to a desired site. The placing of a device can be by any
pharmaceutically accepted means such as by swallowing, retaining it
within the mouth until the drug has been dispensed, placing it
within the buccal cavity, inserting, implanting, attaching, etc.
These and other methods of administration are known in the art.
[0048] The term "anti-cancer agent" refers to an agent that either
inhibits the growth of cancerous cells, or causes the death of
cancerous cells. Known anti-cancer agents include, e.g., nucleotide
and nucleoside analogs, adjunct antineoplastic agents, alkylating
agents, etc. See, Physician's Desk Reference, 55th Edition, Medical
Economics, Montvale, N.J., USA (2001).
[0049] The term "amino" refers to --NH.sub.2. The amino group can
be optionally substituted as defined herein for the term
"substituted." The term "alkylamino" refers to --NR.sub.2, wherein
at least one R is alkyl and the second R is alkyl or hydrogen. The
term "acylamino" refers to N(R)C(.dbd.O)R, wherein each R is
independently hydrogen, alkyl, or aryl.
[0050] The term "alkyl" refers to a C.sub.1-C.sub.18 hydrocarbon
containing normal, secondary, tertiary or cyclic carbon atoms.
Examples are methyl, ethyl, 1-propyl, 2-propyl, 1-butyl,
2-methyl-1-propyl(iso-butyl, --CH.sub.2CH(CH.sub.3).sub.2),
2-butyl(sec-butyl, --CH(CH.sub.3)CH.sub.2CH.sub.3),
2-methyl-2-propyl(tert-butyl, --C(CH.sub.3).sub.3), 1-pentyl,
2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl,
3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl,
2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,
3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl,
3,3-dimethyl-2-butyl.
[0051] The alkyl can be a monovalent hydrocarbon radical, as
described and exemplified above, or it can be a divalent
hydrocarbon radical (i.e., alkylene).
[0052] The alkyl can optionally be substituted with one or more
alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl,
heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino,
alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy,
carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl,
alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido,
benzenesulfinyl, benzenesulfonamido, benzenesulfonyl,
benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl,
benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate,
isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino,
thiosulfo, NR.sup.xR.sup.y and/or COOR.sup.x, wherein each R.sup.x
and R.sup.y are independently H, alkyl, alkenyl, aryl, heteroaryl,
heterocycle, cycloalkyl or hydroxy. The alkyl can optionally be
interrupted with one or more non-peroxide oxy (--O--), thio
(--S--), imino (--N(H)--), methylene dioxy (--OCH.sub.2O--),
carbonyl (--C(.dbd.O)--), carboxy (--C(.dbd.O)O--), carbonyldioxy
(--OC(.dbd.O)O--), carboxylato (--OC(.dbd.O)--), imino (C.dbd.NH),
sulfinyl (SO) or sulfonyl (SO.sub.2). Additionally, the alkyl can
optionally be at least partially unsaturated, thereby providing an
alkenyl.
[0053] The term "alkylene" refers to a saturated, branched or
straight chain or cyclic hydrocarbon radical of 1-18 carbon atoms,
and having two monovalent radical centers derived by the removal of
two hydrogen atoms from the same or different carbon atoms of a
parent alkane. Typical alkylene radicals include, but are not
limited to: methylene (--CH.sub.2--) 1,2-ethylene
(--CH.sub.2CH.sub.2--), 1,3-propylene
(--CH.sub.2CH.sub.2CF.sub.12--), 1,4-butylene
(--CH.sub.2CH.sub.2CH.sub.2CH.sub.2--), and the like.
[0054] The alkylene can optionally be substituted with one or more
alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl,
heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino,
alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy,
carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl,
alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido,
benzenesulfinyl, benzenesulfonamido, benzenesulfonyl,
benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl,
benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate,
isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino,
thiosulfo, NR.sup.xR.sup.y and/or COOR.sup.x, wherein each R.sup.x
and R.sup.y are independently H, alkyl, alkenyl, aryl, heteroaryl,
heterocycle, cycloalkyl or hydroxy. Additionally, the alkylene can
optionally be interrupted with one or more non-peroxide oxy
(--O--), thio (--S--), imino (--N(H)--), methylene dioxy
(--OCH.sub.2O--), carbonyl (--C(.dbd.O)--), carboxy
(--C(.dbd.O)O--), carbonyldioxy (--OC(.dbd.O)O--), carboxylato
(--OC(.dbd.O)--), imine (C.dbd.NH), sulfinyl (SO) or sulfonyl
(SO.sub.2). Moreover, the alkylene can optionally be at least
partially unsaturated, thereby providing an alkenylene.
[0055] The term "alkenylene" refers to an unsaturated, branched or
straight chain or cyclic hydrocarbon radical of 2-18 carbon atoms,
and having two monovalent radical centers derived by the removal of
two hydrogen atoms from the same or two different carbon atoms of a
parent alkene. Typical alkenylene radicals include, but are not
limited to: 1,2-ethenylene (--CH.dbd.CH--).
[0056] The alkenylene can optionally be substituted with one or
more alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl,
heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl,
amino, imino, alkylamino, acylamino, nitro, trifluoromethyl,
trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio,
alkylsulfinyl, alkylsulfonyl, cyano, acetamido, acetoxy, acetyl,
benzamido, benzenesulfinyl, benzenesulfonamido, benzenesulfonyl,
benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl,
benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate,
isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino,
thiosulfo, NR.sup.xR.sup.y and/or COOR.sup.x, wherein each R.sup.x
and R.sup.y are independently H, alkyl, alkenyl, aryl, heteroaryl,
heterocycle, cycloalkyl or hydroxy. Additionally, The alkenylene
can optionally be interrupted with one or more non-peroxide oxy
(--O--), thio (--S--), imino (--N(H)--), methylene dioxy
(--OCH.sub.2O--), carbonyl (--C(.dbd.O)--), carboxy
(--C(.dbd.O)O--), carbonyldioxy (--OC(.dbd.O)O--), carboxylato
(--OC(.dbd.O)--), imine (C.dbd.NH), sulfinyl (SO) or sulfonyl
(SO.sub.2).
[0057] The term "alkoxy" refers to the group alkyl-O--, where alkyl
is defined herein. Preferred alkoxy groups include, e.g., methoxy,
ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy,
n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.
[0058] The alkoxy can optionally be substituted with one or more
halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl,
heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino,
alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy,
carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl,
alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido,
benzenesulfinyl, benzenesulfonamido, benzenesulfonyl,
benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl,
benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate,
isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino,
thiosulfo, NR.sup.xR.sup.y and/or COOR.sup.x, wherein each R.sup.x
and R.sup.y are independently H, alkyl, alkenyl, aryl, heteroaryl,
heterocycle, cycloalkyl, or hydroxy.
[0059] The term "aryl" refers to an unsaturated aromatic
carbocyclic group of from 6 to 20 carbon atoms having a single ring
(e.g., phenyl) or multiple condensed (fused) rings, wherein at
least one ring is aromatic (e.g., naphthyl, dihydrophenanthrenyl,
fluorenyl, or anthryl). Preferred aryls include phenyl, naphthyl
and the like. The aryl can optionally be a divalent radical,
thereby providing an arylene.
[0060] The aryl can optionally be substituted with one or more
alkyl, alkenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl,
aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl,
alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro,
trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto,
thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamido,
acetoxy, acetyl, benzamido, benzenesulfinyl, benzenesulfonamido,
benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino,
benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio,
carbamoyl, carbamate, isocyannato, sulfamoyl, sulfinamoyl, sulfino,
sulfo, sulfoamino, thiosulfo, NR.sup.xR.sup.y and/or COOR.sup.x,
wherein each R.sup.x and R.sup.y are independently H, alkyl,
alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl, or hydroxy.
[0061] The term "carbocycle" refers to a saturated, unsaturated or
aromatic ring having 3 to 8 carbon atoms as a monocycle, 7 to 12
carbon atoms as a bicycle, and up to about 30 carbon atoms as a
polycycle. Monocyclic carbocycles typically have 3 to 6 ring atoms,
still more typically 5 or 6 ring atoms. Bicyclic carbocycles have 7
to 12 ring atoms, e.g., arranged as a bicyclo [4,5], [5,5], [5,6]
or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6]
or [6,6] system. Examples of carbocycles include cyclopropyl,
cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl,
1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl,
1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl, spiryl and naphthyl.
The carbocycle can be optionally substituted as described above for
alkyl groups.
[0062] The term "carboxyl" refers to --COOH.
[0063] All chiral, diastereomeric, racemic forms of a structure are
intended, unless a particular stereochemistry or isomeric form is
specifically indicated. Compounds used in the present invention can
include enriched or resolved optical isomers at any or all
asymmetric atoms as are apparent from the depictions, at any degree
of enrichment. Both racemic and diastereomeric mixtures, as well as
the individual optical isomers can be isolated or synthesized so as
to be substantially free of their enantiomeric or diastereomeric
partners, and these are all within the scope of the invention.
[0064] The term "chemically feasible" refers to a bonding
arrangement or a compound where the generally understood rules of
organic structure are not violated; for example a structure within
a definition of a claim that would contain in certain situations a
pentavalent carbon atom that would not exist in nature would be
understood to not be within the claim.
[0065] When a substituent is specified to be an atom or atoms of
specified identity, "or a bond", a configuration is referred to
when the substituent is "a bond" that the groups that are
immediately adjacent to the specified substituent are directly
connected to each other by a chemically feasible bonding
configuration.
[0066] The phrase "compounds of the disclosure" refer to compounds
of Formula I and pharmaceutically acceptable enantiomers,
diastereomers, and salts thereof. Similarly, references to
intermediates, are meant to embrace their salts where the context
so permits.
[0067] The term "cycloalkyl" refers to cyclic alkyl groups of from
3 to 20 carbon atoms having a single cyclic ring or multiple
condensed rings. Such cycloalkyl groups include, by way of example,
single ring structures such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclooctyl, and the like, or multiple ring structures
such as adamantanyl, and the like.
[0068] The cycloalkyl can optionally be substituted with one or
more alkyl, alkenyl, alkoxy, halo, haloalkyl, hydroxy,
hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl,
alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro,
trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto,
thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamido,
acetoxy, acetyl, benzamido, benzenesulfinyl, benzenesulfonamido,
benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino,
benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio,
carbamoyl, carbamate, isocyannato, sulfamoyl, sulfinamoyl, sulfino,
sulfo, sulfoamino, thiosulfo, NR.sup.xR.sup.y and/or COOR.sup.x,
wherein each R.sup.x and R.sup.y are independently H, alkyl,
alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl, or hydroxy.
[0069] The cycloalkyl can optionally be at least partially
unsaturated, thereby providing a cycloalkenyl. Additionally, the
cycloalkyl can optionally be a divalent radical, thereby providing
a cycloalkylene.
[0070] The term "delivery" refers to the release of a drug from a
device comprising that drug into an environment surrounding the
device. The environment into which the drug so released may or may
not be the ultimate site of activity for that drug. In some
instances, the released drug may need to be transported to its
ultimate site of activity.
[0071] The term "derivative or analogue" of a compound refers to a
chemically modified compound wherein the chemical modification
takes place at one or more functional groups of the compound and
for on an aromatic, alicyclic, or heterocyclic structures, when
present. The derivative or analogue however is expected to retain
the pharmacological activity of the compound from which it is
derived.
[0072] The term "an effective amount" refers to an amount
sufficient to effect beneficial or desired results. An effective
amount can be administered in one or more administrations,
applications, or dosages. Determination of an effective amount for
a given administration is well within the ordinary skill in the
pharmaceutical arts.
[0073] The term "exchanged" is intended to indicate that in between
two or more adjacent carbon atoms, and the hydrogen atoms to which
they are attached (e.g., methyl (CH.sub.3), methylene (CH.sub.2),
or methine (CH)), indicated in the expression using "interrupted"
is inserted with a selection from the indicated group(s), provided
that the each of the indicated atoms' normal valency is not
exceeded, and that the interruption results in a stable compound.
Such suitable indicated groups include, e.g., with one or more
non-peroxide oxy (--O--), thio (--S--), imino (--N(H)--), methylene
dioxy (--OCH.sub.2O--), carbonyl (--C(.dbd.O)--), carboxy
(--C(.dbd.O)O--), carbonyldioxy (--OC(.dbd.O)O--), carboxylato
(--OC(.dbd.O)--), imino (C.dbd.NH), sulfinyl (SO) and sulfonyl
(SO.sub.2).
[0074] The term "halo" refers to fluoro, chloro, bromo, and iodo.
Similarly, the term "halogen" refers to fluorine, chlorine,
bromine, and iodine.
[0075] The term "haloalkyl" refers to alkyl as defined herein
substituted by 1-4 halo groups as defined herein, which may be the
same or different. Representative haloalkyl groups include, by way
of example, trifluoromethyl, 3-fluorododecyl,
12,12,12-trifluorododecyl, 2-bromooctyl, 3-bromo-6-chloroheptyl,
and the like.
[0076] The term "heteroaryl" is defined herein as a monocyclic,
bicyclic, or tricyclic ring system containing one, two, or three
aromatic rings and containing at least one nitrogen, oxygen, or
sulfur atom in an aromatic ring, and which can be unsubstituted or
substituted. The heteroaryl can optionally be a divalent radical,
thereby providing a heteroarylene.
[0077] Examples of heteroaryl groups include, but are not limited
to, 2H-pyrrolyl, 3H-indolyl, 4H-quinolizinyl, 4nH-carbazolyl,
acridinyl, benzo[b]thienyl, benzothiazolyl, .beta.-carbolinyl,
carbazolyl, chromenyl, cinnaolinyl, dibenzo[b,d]furanyl, furazanyl,
furyl, imidazolyl, imidizolyl, indazolyl, indolisinyl, indolyl,
isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl,
naphthyridinyl, naptho[2,3-b], oxazolyl, perimidinyl,
phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,
phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,
pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl,
pyridyl, pyrimidinyl, pyrimidinyl, pyrrolyl, quinazolinyl,
quinolyl, quinoxalinyl, thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, triazolyl, and xanthenyl. In one embodiment the term
"heteroaryl" denotes a monocyclic aromatic ring containing five or
six ring atoms containing carbon and 1, 2, 3, or 4 heteroatoms
independently selected from the group non-peroxide oxygen, sulfur,
and N(Z) wherein Z is absent or is H, O, alkyl, phenyl, or benzyl.
In another embodiment heteroaryl denotes an ortho-fused bicyclic
heterocycle of about eight to ten ring atoms derived therefrom,
particularly a benz-derivative or one derived by fusing a
propylene, or tetramethylene diradical thereto.
[0078] The heteroaryl can optionally be substituted with one or
more alkyl, alkenyl, alkoxy, halo, haloalkyl, hydroxy,
hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl,
alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro,
trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto,
thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamido,
acetoxy, acetyl, benzamido, benzenesulfinyl, benzenesulfonamido,
benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino,
benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio,
carbamoyl, carbamate, isocyannato, sulfamoyl, sulfinamoyl, sulfino,
sulfo, sulfoamino, thiosulfo, NR.sup.xR.sup.y and/or COOR.sup.x,
wherein each R.sup.x and R.sup.y are independently H, alkyl,
alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl, or hydroxy.
[0079] The term "heterocycle" or "heterocyclyl" refers to a
saturated or partially unsaturated ring system, containing at least
one heteroatom selected from the group oxygen, nitrogen, and
sulfur, and optionally substituted with alkyl, or
C(.dbd.O)OR.sup.b, wherein R.sup.b is hydrogen or alkyl. Typically
heterocycle is a monocyclic, bicyclic, or tricyclic group
containing one or more heteroatoms selected from the group oxygen,
nitrogen, and sulfur. A heterocycle group also can contain an oxo
group (.dbd.O) attached to the ring. Non-limiting examples of
heterocycle groups include 1,3-dihydrobenzofuran, 1,3-dioxolane,
1,4-dioxane, 1,4-dithiane, 2H-pyran, 2-pyrazoline, 4H-pyran,
chromanyl, imidazolidinyl, imidazolinyl, indolinyl, isochromanyl,
isoindolinyl, morpholine, piperazinyl, piperidine, piperidyl,
pyrazolidine, pyrazolidinyl, pyrazolinyl, pyrrolidine, pyrroline,
quinuclidine, and thiomorpholine. The heterocycle can optionally be
a divalent radical, thereby providing a heterocyclene.
[0080] The heterocycle can optionally be substituted with one or
more alkyl, alkenyl, alkoxy, halo, haloalkyl, hydroxy,
hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl,
alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro,
trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto,
thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamido,
acetoxy, acetyl, benzamido, benzenesulfinyl, benzenesulfonamido,
benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino,
benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio,
carbamoyl, carbamate, isocyannato, sulfamoyl, sulfinamoyl, sulfino,
sulfo, sulfoamino, thiosulfo, NR.sup.xR.sup.y and/or COOR.sup.x,
wherein each R.sup.x and R.sup.y are independently H, alkyl,
alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl, or hydroxy.
[0081] Examples of nitrogen heterocycles and heteroaryls include,
but are not limited to, pyrrole, imidazole, pyrazole, pyridine,
pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole,
indazole, purine, quinolizine, isoquinoline, quinoline,
phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline,
pteridine, carbazole, carboline, phenanthridine, acridine,
phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine,
phenothiazine, imidazolidine, imidazoline, piperidine, piperazine,
indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like
as well as N-alkoxy-nitrogen containing heterocycles.
[0082] The term "hydrate" refers to the complex where the solvent
molecule is water.
[0083] The term "include," "for example," "such as," and the like
are used illustratively and are not intended to limit the present
invention.
[0084] The term "interrupted" indicates that another group is
inserted between two adjacent carbon atoms (and the hydrogen atoms
to which they are attached (e.g., methyl (CH.sub.3), methylene
(CH.sub.2) or methine (CH))) of a particular carbon chain being
referred to in the expression using the term "interrupted, provided
that each of the indicated atoms' normal valency is not exceeded,
and that the interruption results in a stable compound. Suitable
groups that can interrupt a carbon chain include, e.g., with one or
more non-peroxide oxy (--O--), thio (--S--), imino (--N(H)--),
methylene dioxy (--OCH.sub.2O--), carbonyl (--C(.dbd.O)--), carboxy
(--C(.dbd.O)O--), carbonyldioxy (--OC(.dbd.O)O--), carboxylato
(--OC(.dbd.O)--), imine (C.dbd.NH), sulfinyl (SO) and sulfonyl
(SO.sub.2). Alkyl groups can be interrupted by one or more (e.g.,
1, 2, 3, 4, 5, or about 6) of the aforementioned suitable groups.
The site of interruption can also be between a carbon atom of an
alkyl group and a carbon atom to which the alkyl group is
attached.
[0085] As to any of the groups described herein, which contain one
or more substituents, it is understood, of course, that such groups
do not contain any substitution or substitution patterns which are
sterically impractical and/or synthetically non-feasible. In
addition, the compounds of this disclosed subject matter include
all stereochemical isomers arising from the substitution of these
compounds.
[0086] Selected substituents within the compounds described herein
are present to a recursive degree. In this context, "recursive
substituent" means that a substituent may recite another instance
of itself. Because of the recursive nature of such substituents,
theoretically, a large number may be present in any given claim.
One of ordinary skill in the art of medicinal chemistry and organic
chemistry understands that the total number of such substituents is
reasonably limited by the desired properties of the compound
intended. Such properties include, by of example and not
limitation, physical properties such as molecular weight,
solubility or log P, application properties such as activity
against the intended target, and practical properties such as ease
of synthesis.
[0087] Recursive substituents are an intended aspect of the
disclosed subject matter. One of ordinary skill in the art of
medicinal and organic chemistry understands the versatility of such
substituents. To the degree that recursive substituents are present
in a claim of the disclosed subject matter, the total number will
be determined as set forth above.
[0088] The term "metabolite" refers to any compound of the formula
(I) produced in vivo or in vitro from the parent drug, or its
prodrugs. The term "molecular weight" refers to a weight-average
molecular weight, as is well known in the art. The term "oxo"
refers to .dbd.O.
[0089] The term "pharmaceutically acceptable" refers to those
compounds, materials, compositions, and/or dosage forms that are,
within the scope of sound medical judgment, suitable for use in
contact with the tissues of human beings and animals without
excessive toxicity, irritation, allergic response, or other
problems or complications commensurate with a reasonable
benefit/risk ratio. Several pharmaceutically acceptable ingredients
are known in the art and official publications such as The United
States Pharmacoepia describe the analytical criteria to assess the
pharmaceutical acceptability of numerous ingredients of
interest.
[0090] The term "pharmaceutically acceptable salts" refers to ionic
compounds, wherein a parent non-ionic compound is modified by
making acid or base salts thereof. Examples of pharmaceutically
acceptable salts include mineral or organic acid salts of basic
residues such as amines; alkali or organic salts of acidic residues
such as carboxylic acids; and the like. The pharmaceutically
acceptable salts include conventional non-toxic salts and
quaternary ammonium salts of the parent compound formed, for
example, from non-toxic inorganic or organic acids. Non-toxic salts
can include those derived from inorganic acids such as
hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic,
phosphoric, nitric and the like. Salts prepared from organic acids
can include those such as acetic, 2-acetoxybenzoic, ascorbic,
benzenesulfonic, benzoic, citric, ethanesulfonic, ethane
disulfonic, formic, fumaric, gentisinic, glucaronic, gluconic,
glutamic, glycolic, hydroxymaleic, isethionic, isonicotinic,
lactic, maleic, malic, mesylate or methanesulfonic, oxalic, pamoic
(1,1'-methylene-bis-(2-hydroxy-3-naphthoate)), pantothenic,
phenylacetic, propionic, salicylic, sulfanilic, toluenesulfonic,
stearic, succinic, tartaric, bitartaric, and the like. Certain
compounds can form pharmaceutically acceptable salts with various
amino acids. For a review on pharmaceutically acceptable salts,
see, e.g., Berge et al., J. Pharm. Sci. 1977, 66(1), 1-19, which is
incorporated herein by reference.
[0091] The pharmaceutically acceptable salts of the compounds
described herein can be synthesized from the parent compound, which
contains a basic or acidic moiety, by conventional chemical
methods. Generally, such salts can be prepared by reacting the free
acid or base forms of these compounds with a stoichiometric amount
of the appropriate base or acid in water or in an organic solvent,
or in a mixture of the two; generally, nonaqueous media like ether,
ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
Lists of many suitable salts are found in Remington: The Science
and Practice of Pharmacy, 21.sup.st edition, Lippincott, Williams
& Wilkins, (2005).
[0092] It will be appreciated by those skilled in the art that
compounds useful in the disclosed subject matter having a chiral
center may exist in and be isolated in optically active and racemic
forms. Some compounds may exhibit polymorphism. It is to be
understood that the presently disclosed subject matter encompasses
any racemic, optically-active, polymorphic, or stereoisomeric form,
or mixtures thereof, of a compound of the presently disclosed
subject matter, which possess the useful properties described
herein, it being well known in the art how to prepare optically
active forms (for example, by resolution of the racemic form by
recrystallization techniques, by synthesis from optically-active
starting materials, by chiral synthesis, or by chromatographic
separation using a chiral stationary phase) and how to determine
anticancer activity using the standard tests described herein, or
using other similar tests which are well known in the art.
[0093] One diastereomer of a compound disclosed herein may display
superior activity compared with the other. When required,
separation of the racemic material can be achieved by HPLC using a
chiral column or by a resolution using a resolving agent such as
camphonic chloride as in Tucker et al., J. Med. Chem., 37, 2437
(1994). A chiral compound described herein may also be directly
synthesized using a chiral catalyst or a chiral ligand, e.g.,
Huffman et al., J. Org. Chem., 60:1590 (1995).
[0094] The terms "prevent," "preventative," "prevention,"
"protect," and "protection" refer to medical procedures that keep
the malcondition from occurring in the first place. The terms mean
that there is no or a lessened development of disease or disorder
where none had previously occurred, or no further disorder or
disease development if there had already been development of the
disorder or disease.
[0095] The term "prodrug" refers to any pharmaceutically acceptable
form of compound of the formula I, which, upon administration to a
patient, provides a compound of the formula I. Pharmaceutically
acceptable prodrugs refer to a compound that is metabolized, for
example hydrolyzed or oxidized, in the host to form a compound of
the formula I. Typical examples of prodrugs include compounds that
have biologically labile protecting groups on a functional moiety
of the active compound. Prodrugs include compounds that can be
oxidized, reduced, aminated, deaminated, hydroxylated,
dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated,
acylated, deacylated, phosphorylated, dephosphorylated to produce
the active compound.
[0096] The prodrug may be prepared with the objective(s) of
improved chemical stability, improved patient acceptance and
compliance, improved bioavailability, prolonged duration of action,
improved organ selectivity (including improved brain penetrance),
improved formulation (e.g., increased hydrosolubility), and/or
decreased side effects (e.g., toxicity). See e.g. T. Higuchi and V.
Stella, "Prodrugs as Novel Delivery Systems", Vol. 14 of the A.C.S.
Symposium Series; Bioreversible Carriers in Drug Design, ed. Edward
B. Roche, American Pharmaceutical Association and Pergamon Press,
(1987). Prodrugs include, but are not limited to, compounds derived
from compounds of formula I wherein hydroxy, amine or sulfhydryl
groups, if present, are bonded to any group that, when administered
to the subject, cleaves to form the free hydroxyl, amino or
sulfhydryl group, respectively. Selected examples include, but are
not limited to, biohydrolyzable amides and biohydrolyzable esters
and biohydrolyzable carbamates, carbonates, acetate, formate and
benzoate derivatives of alcohol and amine functional groups.
[0097] The prodrug can be readily prepared from the compounds of
Formula (I) using methods known in the art. See, for example,
Notari, R. E., "Theory and Practice of Prodrug Kinetics," Methods
in Enzymology, 112:309 323 (1985); Bodor, N., "Novel Approaches in
Prodrug Design," Drugs of the Future, 6(3):165 182 (1981); and
Bundgaard, H., "Design of Prodrugs: Bioreversible-Derivatives for
Various Functional Groups and Chemical Entities," in Design of
Prodrugs (H. Bundgaard, ed.), Elsevier, N.Y. (1985); Burger's
Medicinal Chemistry and Drug Chemistry, Fifth Ed., Vol. 1, pp.
172-178, 949-982 (1995).
[0098] The term "solvate" refers to a complex of variable
stoichiometry formed by a solute (in this invention, a compound of
formula 1, or a salt or physiologically functional derivative
thereof) and a solvent. Such solvents, for the purpose of the
invention, should not interfere with the biological activity of the
solute. Non-limiting examples of suitable solvents include, but are
not limited to water, methanol, ethanol, and acetic acid.
Preferably the solvent used is a pharmaceutically acceptable
solvent. Non-limiting examples of suitable pharmaceutically
acceptable solvents include water, ethanol, and acetic acid.
[0099] The term "stereoisomer" refers to a compound made up of the
same atoms bonded by the same bonds but having different
three-dimensional structures, which are not interchangeable.
[0100] The term "substituted" is intended to indicate that one or
more hydrogens on the atom indicated in the expression using
"substituted" is replaced with a selection from the indicated
group(s), provided that the indicated atom's normal valency is not
exceeded, and that the substitution results in a stable compound.
Suitable indicated groups include, e.g., alkyl, alkenyl,
alkylidenyl, alkenylidenyl, alkoxy, halo, haloalkyl, hydroxy,
hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl,
acyloxy, alkoxycarbonyl, amino, imino, alkylamino, acylamino,
nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl,
keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano,
acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl,
benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl,
benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl,
benzylthio, carbamoyl, carbamate, isocyanato, sulfamoyl,
sulfinamoyl, sulfino, sulfo, sulfoamino, thiosulfo, NR.sup.xR.sup.y
and/or COOR.sup.x, wherein each R.sup.x and R.sup.y are
independently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle,
cycloalkyl, or hydroxy. When a substituent is oxo (i.e., .dbd.O) or
thioxo (i.e., .dbd.S) group, then two hydrogens on the atom are
replaced. The term "sulfonyl" refers to --SO.sub.2--.
[0101] The term "tautomer" refers to a proton shift from one atom
of a molecule to another atom of the same molecule.
[0102] The term "therapeutically effective amount" is intended to
include an amount of a compound described herein, or an amount of
the combination of compounds described herein, e.g., to treat or
prevent the disease or disorder, or to treat the symptoms of the
disease or disorder, in a host. The combination of compounds is
preferably a synergistic combination. Synergy, as described for
example by Chou and Talalay, Adv. Enzyme Regul., 22:27 (1984),
occurs when the effect of the compounds when administered in
combination is greater than the additive effect of the compounds
when administered alone as a single agent. In general, a
synergistic effect is most clearly demonstrated at suboptimal
concentrations of the compounds. Synergy can be in terms of lower
cytotoxicity, increased activity, or some other beneficial effect
of the combination compared with the individual components.
[0103] The terms "therapy," and "therapeutic" refer to either
"treatment" or "prevention," thus, agents that either treat damage
or prevent damage are "therapeutic."
[0104] The terms "treating" or "treat" or "treatment" refer to
obtaining a desired pharmacologic and/or physiologic effect. The
effect may be prophylactic in terms of completely or partially
preventing a disease or symptom thereof and/or may be therapeutic
in terms of a partial or complete cure for a disease and/or adverse
affect attributable to the disease. As used herein, the term
"treatment," covers any treatment of a disease in a mammal,
particularly in a human, and includes: (a) preventing the disease
from occurring in a subject which may be predisposed to the disease
but has not yet been diagnosed as having it; (b) inhibiting the
disease, i.e., arresting its development; and (c) relieving the
disease, i.e., causing regression of the disease.
[0105] In addition, where features or aspects of the invention are
described in terms of Markush groups, those skilled in the art will
recognize that the invention is also thereby described in terms of
any individual member or subgroup of members of the Markush group.
For example, if X is described as selected from the group
consisting of bromine, chlorine, and iodine, claims for X being
bromine and claims for X being bromine and chlorine are fully
described. Moreover, where features or aspects of the invention are
described in terms of Markush groups, those skilled in the art will
recognize that the invention is also thereby described in terms of
any combination of individual members or subgroups of members of
Markush groups. Thus, for example, if X is described as selected
from the group consisting of bromine, chlorine, and iodine, and Y
is described as selected from the group consisting of methyl,
ethyl, and propyl, claims for X being bromine and Y being methyl
are fully described.
[0106] In various embodiments, the compound or set of compounds,
such as are used in the inventive methods, can be any one of any of
the combinations and/or sub-combinations of the above-listed
embodiments.
[0107] Asymmetric carbon atoms may be present in the compounds
described. All such isomers, including diastereomers and
enantiomers, as well as the mixtures thereof are intended to be
included in the scope of the recited compound. In certain cases,
compounds can exist in tautomeric forms. All tautomeric forms are
intended to be included in the scope. Likewise, when compounds
contain an alkenyl or alkenylene group, there exists the
possibility of cis- and trans-isomeric forms of the compounds. Both
cis- and trans-isomers, as well as the mixtures of cis- and
trans-isomers, are contemplated. Thus, reference herein to a
compound includes all of the aforementioned isomeric forms unless
the context clearly dictates otherwise.
[0108] Various forms are included in the embodiments, including
polymorphs, solvates, hydrates, conformers, salts, and prodrug
derivatives. A polymorph is a composition having the same chemical
formula, but a different structure. A solvate is a composition
formed by solvation (the combination of solvent molecules with
molecules or ions of the solute). A hydrate is a compound formed by
an incorporation of water. A conformer is a structure that is a
conformational isomer. Conformational isomerism is the phenomenon
of molecules with the same structural formula but different
conformations (conformers) of atoms about a rotating bond. Salts of
compounds can be prepared by methods known to those skilled in the
art. For example, salts of compounds can be prepared by reacting
the appropriate base or acid with a stoichiometric equivalent of
the compound. A prodrug is a compound that undergoes
biotransformation (chemical conversion) before exhibiting its
pharmacological effects. For example, a prodrug can thus be viewed
as a drug containing specialized protective groups used in a
transient manner to alter or to eliminate undesirable properties in
the parent molecule. Thus, reference herein to a compound includes
all of the aforementioned forms unless the context clearly dictates
otherwise.
[0109] Concentrations, amounts, etc., of various components are
often presented in a range format throughout this disclosure. The
description in range format is merely for convenience and brevity
and should not be construed as an inflexible limitation on the
scope of the claimed invention. Accordingly, the description of a
range should be considered to have specifically disclosed all the
possible subranges as well as individual numerical values within
that range. For example, description of a range such as 1% to 8%
should be considered to have specifically disclosed subranges such
as 1% to 7%, 2% to 8%, 2% to 6%, 3% to 6%, 4% to 8%, 3% to 8% etc.,
as well as individual numbers within that range, such as, 2%, 5%,
7% etc. This construction applies regardless of the breadth of the
range and in all contexts throughout this disclosure.
[0110] In the claims provided herein, the steps specified to be
taken in a claimed method or process may be carried out in any
order without departing from the principles of the invention,
except when a temporal or operational sequence is explicitly
defined by claim language. Recitation in a claim to the effect that
first a step is performed then several other steps are performed
shall be taken to mean that the first step is performed before any
of the other steps, but the other steps may be performed in any
sequence unless a sequence is further specified within the other
steps. For example, claim elements that recite "first A, then B, C,
and D, and lastly E" shall be construed to mean step A must be
first, step E must be last, but steps B, C, and D may be carried
out in any sequence between steps A and E and the process of that
sequence will still fall within the four corners of the claim.
[0111] Furthermore, in the claims provided herein, specified steps
may be carried out concurrently unless explicit claim language
requires that they be carried out separately or as parts of
different processing operations. For example, a claimed step of
doing X and a claimed step of doing Y may be conducted
simultaneously within a single operation, and the resulting process
will be covered by the claim. Thus, a step of doing X, a step of
doing Y, and a step of doing Z may be conducted simultaneously
within a single process step, or in two separate process steps, or
in three separate process steps, and that process will still fall
within the four corners of a claim that recites those three
steps.
[0112] Similarly, except as explicitly required by claim language,
a single substance or component may meet more than a single
functional requirement, provided that the single substance fulfills
the more than one functional requirement as specified by claim
language.
[0113] The compounds described herein can be prepared by any of the
applicable techniques of organic synthesis. Many such techniques
are well known in the art. However, many of the known techniques
are elaborated in Compendium of Organic Synthetic Methods (John
Wiley & Sons, New York) Vol. 1, Ian T. Harrison and Shuyen
Harrison (1971); Vol. 2, Ian T. Harrison and Shuyen Harrison
(1974); Vol. 3, Louis S. Hegedus and Leroy Wade (1977); Vol. 4,
Leroy G. Wade Jr., (1980); Vol. 5, Leroy G. Wade Jr. (1984); and
Vol. 6, Michael B. Smith; as well as March, J., Advanced Organic
Chemistry, 3rd Edition, John Wiley & Sons, New York (1985);
Comprehensive Organic Synthesis, Selectivity, Strategy &
Efficiency in Modern Organic Chemistry, In 9 Volumes, Barry M.
Trost, Editor-in-Chief, Pergamon Press, New York (1993); Advanced
Organic Chemistry, Part B: Reactions and Synthesis, 4th Ed.; Carey
and Sundberg; Kluwer Academic/Plenum Publishers: New York (2001);
Advanced Organic Chemistry, Reactions, Mechanisms, and Structure,
2nd Edition, March, McGraw Hill (1977); Protecting Groups in
Organic Synthesis, 2nd Edition, Greene, T. W., and Wutz, P. G. M.,
John Wiley & Sons, New York (1991); and Comprehensive Organic
Transformations, 2nd Edition, Larock, R. C., John Wiley & Sons,
New York (1999). Exemplary methods of making the compounds
described herein are described herein in the examples below.
[0114] Obviously, numerous modifications and variations of the
presently disclosed subject matter are possible in light of the
above teachings. It is therefore to be understood that within the
scope of the claims, the disclosed subject matter may be practiced
otherwise than as specifically described herein.
[0115] Specific ranges, values, and embodiments provided herein are
for illustration purposes only and do not otherwise limit the scope
of the disclosed subject matter, as defined by the claims.
[0116] It should be understood that the present disclosure
encompasses all stereochemical isomeric forms, or mixtures thereof,
which possess the ability to kill cancer cells and/or inhibit
growth of cancer cells. Enantiomers of the present disclosure may
be resolved by methods known to those skilled in the art, for
example, by formation of diastereoisomeric salts which may be
separated by crystallization, gas-liquid or liquid chromatography,
or selective reaction of one enantiomer with an enantiomer-specific
reagent. It will be appreciated that where the desired enantiomer
is converted into another chemical entity by a separation
technique, then an additional step is required to form the desired
enantiomeric form. Alternatively, specific enantiomers may be
synthesized by asymmetric synthesis using optically active
reagents, substrates, catalysts or solvents, or by converting one
enantiomer into the other by asymmetric transformation.
[0117] Certain compounds of the present disclosure may also exist
in different stable conformational forms which may be separable.
Torsional asymmetry due to restricted rotation about an asymmetric
single bond, for example because of steric hindrance or ring
strain, may permit separation of different conformers. The present
disclosure includes each conformational isomer of these compounds
and mixtures thereof.
[0118] Certain compounds of the present disclosure may exist in
zwitterionic form and the present disclosure includes each
zwitterionic form of these compounds and mixtures thereof.
[0119] The starting materials useful to synthesize the compounds of
the present disclosure are known to those skilled in the art and
can be readily manufactured or are commercially available.
[0120] The following methods set forth below are provided for
illustrative purposes and are not intended to limit the scope of
the claimed disclosure. It will be recognized that it may be
necessary to prepare such a compound in which a functional group is
protected using a conventional protecting group then to remove the
protecting group to provide a compound of the present disclosure.
The details concerning the use of protecting groups in accordance
with the present disclosure are known to those skilled in the
art.
[0121] The invention relates to synthesis of anticancer compounds
of (fluorophenyl)quinolin-4-one derivatives of formula
##STR00006##
[0122] As mentioned above CHM-2133-P exhibited excellent antitumor
activity, through both oral and intravenous administration, which
is very likely related to its unique structure that was made up of
the following three functional groups: Firstly, the phosphate group
located on the 4-position of its quinoline ring. As stated in our
previous report that pharmacokinetic study of CHM-2133-P confirmed
its rapid bio-conversion into its active molecule CHM-2133
following administration. Alkaline phosphatase is known to
over-expressed on the extracellular space of specific tumor cells
such as ovarian and hepatoma cells, therefore the introduction of a
phosphate group appears to be a reasonable strategy for target
delivery.
[0123] Secondly, the methylenedioxy moiety bridges the 5- and
6-position of its quinoline ring, which could form an orthoquinone
upon metabolism, and could be subsequently metabolized into more
cytotoxic metabolites in hypoxia cells. Because severe hypoxia is a
common situation of locally advanced solid tumor, the incorporation
of methylenedioxy moiety to fight tumors becomes a meaningful
approach.
[0124] Thirdly, the fluorine atom located on the 2-phenyl group. To
certain medicines, the unordinary nature of fluorine was reported
to impart a variety of properties including enhanced potency,
improved duration of action and attenuation of biliary
clearance.
[0125] Meanwhile, established SAR indicated the existence of a
group with lone pair electrons (for instance, OCH.sub.3, NRR, Cl,
F) at both the 6-position of quinoline ring and 3'-position of
2-phenyl group enhanced the cytotoxicity of 2-PQs. Bearing the
structural characteristics of CHM-2133-P in mind, the inventor
designed compounds 16-21, 37-45 (FIG. 2) and their phosphates as
target compounds based on the following principles: (1) The
presence of a O--R group at 6-position of quinoline ring. (2) The
presence of a fluorine atom at the 2-phenyl group. (3) Readiness to
be metabolized into orthoquinone in vivo and (4) should be new
2-PQs that were not synthesized before. For illustration, methods
of synthesizing target compounds 16-21, 37-45 and evaluating their
cytotoxicity are disclosed. Drug candidate compounds may be
converted into water soluble, sodium salt of phosphate derivatives
for improved hydrophilicity. All the synthesized phosphate
derivatives may be evaluated for in vivo anticancer activity.
Examples
[0126] Without intent to limit the scope of the invention,
exemplary instruments, apparatus, methods and their related results
according to the embodiments of the present invention are given
below. Note that titles or subtitles may be used in the examples
for convenience of a reader, which in no way should limit the scope
of the invention. Moreover, certain theories are proposed and
disclosed herein; however, in no way they, whether they are right
or wrong, should limit the scope of the invention so long as the
invention is practiced according to the invention without regard
for any particular theory or scheme of action.
General Structures of Compounds
A-Series (Scheme 1-Scheme 5)
##STR00007##
[0127] B-Series (Scheme 6-Scheme 10)
##STR00008##
[0128] C-Series (Scheme 11 and Scheme 12)
##STR00009##
[0129] D-Series (Scheme 13)
##STR00010##
[0130] I. A Series
Chemical Synthesis
[0131] Scheme 1: Synthesis of Compounds 16-24. The synthesis of
5,6,7,2',3',4'-substituted 2-phenylquinolin-4-ones (16-24) was
illustrated in Scheme 1. First, 3,4,5-substituted
1-amino-2-acetylbenzenes (1-3) were reacted separately with
2,3,4-substituted benzoyl chlorides (4-6) to yield the
corresponding amides (7-15) that were subsequently cyclized in
t-BuOH, in the presence of i-BuOK, to afford the desired compounds
(16-24).
[0132] Scheme 2: Synthesis of Starting Compounds 1-3. The starting
compounds 1-3 were not from commercial source, and were prepared
according to Scheme 2. Following a published method,.sup.8
2,3-dimethoxybenzonitrile (25) was subjected to Grignard reaction
by reacting with CH.sub.3MgBr in ether to yield
2,3-dimethoxyacetophenone (26). Compound 26 was then nitrated with
70% HNO.sub.3 to give 2,3-dimethoxy-6-nitroacetophenone (27) which,
without purification, was hydrogenated over Pd/C. The reaction
product was purified by column chromatography to afford
6-amino-2,3-dimethoxyacetophenone (1) whose structure was confirmed
by 2D-NMR spectra.
[0133] 6-Amino-2,3-dimethoxyacetophenone (2) was also prepared
according to published methods. The starting catechol (28) was
acetylated, in microwave oven set at 300 Watt power, by reacting
with mixture of acetic acid (29) and BF.sub.3. Et.sub.2O to yield
2,3-dihydroxyacetophenone (30) which was further reacted with
diiodomethane in DMF, in the presence of K.sub.2CO.sub.3, to afford
2,3-methylenedioxyacetophenone (31). Subsequent nitration of
compound 31 with 70% HNO.sub.3 afforded
2,3-methylenedioxy-6-nitroacetophenone (32). Without purification,
compounds 32 was hydrogenated, and purified with column
chromatography to provide 6-amino-2,3-methylenedioxyacetophenone
(2)..sup.10 Another published method was followed in preparation of
6-amino-3-methoxy-4-benzyloxyacetophenone (3). First, the
benzylation of the starting acetovanillone (33) with benzylbromide
(34) gave 4-benzyloxy-3-methoxyacetophenone (35) which was nitrated
to yield 4-benzyloxy-3-methoxy-6-nitroacetophenone (36)..sup.11 The
so-obtained compound 36 was reduced with SnCl.sub.2 to afford
compound 3.
[0134] Scheme 3: Synthesis of Compounds 37-45. Scheme 3 illustrated
the preparation of designed compounds 37-45. As shown, compounds
16-18 were selectively demethylated by treating with BCl.sub.3 in
CH.sub.2Cl.sub.2, to afford the corresponding
2-(fluorophenyl)-5-hydroxy-6-methoxyquinolin-4-ones (37-39) whose
structures were confirmed by 2D-NMR spectra. Catalytic
hydrogenation of compounds 19-21 yielded
2-(fluorophenyl)-5,6-dihydroxyquinolin-4-ones (40-42), and
similarly, hydrogenation of
7-benzyloxy-2-(fluorophenyl)-6-methoxyquinolin-4-ones (22-24) gave
2-(fluorophenyl)-7-hydroxy-6-methoxyquinolin-4-ones (43-45).
##STR00011##
##STR00012## ##STR00013##
##STR00014##
[0135] Schemes 4-5: Phosphorylation of Compound 38. The
phosphorylation of
2-(3-fluorophenyl)-5-hydroxy-6-methoxyquinoline-4-one (38) was
illustrated in Schemes 4 and 5. Compound 38 was first reacted with
tetrabenzylpyrophosphate (46) in THF in the presence of NaH or
dibenzylphosphite (47) to yield
2-(3-fluorophenyl)-6-methoxyquinoline-4,5-diyl bis(dibenzyl
phosphate) (48). Compound 48 was then subjected to catalytic
hydrogenation in MeOH to give its diphosphoric acid (49). Finally,
compound 49 was converted into water soluble sodium salt (50) by
treatment with NaHCO.sub.3. In the process of purifying compound
48, the coexistence of its dephosphorylated derivative was found.
Presumably as illustrated in Scheme 5, the inductive effect by the
nitrogen atom on the 1-position of quinoline ring facilitated the
selective elimination of phosphate moiety on the 4-position of the
same ring. Upon testing several conditions of reaction led to
selective 4-phosphate elimination of compound 48, it was found that
stirring at room temperature of compound 48 dissolved in MeOH
resulted in precipitation of its monophosphate derivative 51 whose
structure was confirmed by the .sup.1H-NMR chemical shift of its
proton on the 3-position (.delta. 6.27). Finally, using the same
synthetic procedure for compound 50, the hydrogenation of compound
51, followed by treatment with NaHCO.sub.3, resulted in desired
water soluble, sodium salt of monophosphate derivative (52).
##STR00015##
##STR00016##
Examples
[0136] General Experimental Procedures. All of the reagents and
solvents were obtained commercially and used without further
purification. Reactions were monitored by thin-layer
chromatography, using Merck plates with fluorescent indicator (TLC
Silica gel 60 F.sub.254). The following adsorbent was used for
column chromatography: silica gel 60 (Merck, particle size
0.063-0.200 mm). Melting points were determined on a Yanaco MP-500D
melting point apparatus and were uncorrected. IR spectra were
recorded on Shimadzu IRPrestige-21 spectrophotometers as KBr
pellets. NMR spectra were obtained on a Bruker Avance DPX-200
FT-NMR spectrometer in CDCl.sub.3 or DMSO. The following
abbreviations are used: s, singlet; d, doublet; t, triplet; q,
quartet; dd, double doublet and m, multiplet. EI-MS spectra were
measured with an HP 5995 GC-MS instrument. ESI-MS spectra were
measured with a Finnigan LCQ ion-trap mass spectrometer (TSQ
Quantum, Thermo Finnigan Corporation, San Jose, Calif.). Elemental
analyses (C, H, and N) were performed on a Perkin-Elmer 2400 Series
II CHNS/O analyzer, and the results were within .+-.0.4% of the
calculated values.
[0137] N-(2-Acetyl-3,4-dimethoxyphenyl)-2-fluorobenzamide (7). To a
solution of 2-fluorobenzoyl chloride (4), 0.48 g, 2.46 mmol) in 40
mL of dry toluene were added triethylamine (0.5 mL) and compound 1
(0.70 g, 4.43 mmol). The mixture was stirred at 55-60.degree. C.
for 30 min, and then poured into crushed ice, extracted with EtOAc.
The organic layer was washed with brine, dried over MgSO.sub.4 and
evaporated. The crude product was purified by column chromatography
(Silica gel, EtOAc/n-hexane) to give 7 (0.5 g, 1.58 mmol) as a
yellow solid. Yield: 64.1%; mp 106-108.degree. C.; MS (EI, 70 eV):
m/z 317 (M.sup.+); .sup.1H-NMR (DMSO-d.sub.6,200 MHz): .delta. 2.45
(s, 3H), 3.76 (s, 3H), 3.81 (s, 3H), 7.14 (d, J=2.6 Hz, 2H),
7.24-7.34 (m, 2H), 7.52-7.63 (n7, 2H), 10.07 (s, 1H); .sup.13C-NMR
(DMSO-d.sub.6, 50 MHz): .delta. 31.91, 56.52, 61.42, 114.52,
116.70, 121.43, 124.16, 125.06, 126.81, 130.52, 131.50, 133.35 (d,
=8.0 Hz), 145.98, 150.47, 159.61 (d, J=247.5 Hz), 163.19, 201.38;
Anal. calcd for C.sub.17H.sub.16FNO.sub.4: C, 64.35; H, 5.08; N,
4.41. Found: C, 64.31; H, 5.10; N, 4.43.
[0138] N-(2-Acetyl-3,4-dimethoxyphenyl)-3-fluorobenzamide (8) was
obtained from 1 and 3-fluorobenzoyl chloride (5). Yellow solid;
Yield: 65.0%; nip 98-99.degree. C.; MS (EI, 70 eV): m/z 317
(M.sup.+); .sup.1H-NMR (DMSO-d.sub.6,200 MHz): .delta. 2.43 (s,
3H), 3.76 (s, 3H), 3.81 (s, 3H), 7.03-7.15 (m, 2H), 7.39-7.71 (m,
4H), 10.18 (s, 1H); .sup.13C-NMR (DMSO-d.sub.6, 50 MHz): .delta.
31.74, 56.45, 61.38, 114.30, 114.73 (d, J=23 Hz), 119.04 (d, J=21
Hz), 121.98, 124.13, 126.91, 131.12 (d, J=7.5 Hz), 132.27, 136.89
(d, J=6.5 Hz), 145.90, 150.65, 162.40 (d, J=243 Hz), 164.67,
201.22; Anal. calcd for C.sub.17H.sub.16FNO.sub.4: C, 64.35; H,
5.08; N, 4.41. Found: C, 64.34; H, 5.06; N, 4.44.
[0139] N-(2-Acetyl-3,4-dimethoxyphenyl)-4-fluorobenzamide (9) was
obtained from 1 and 4-fluorobenzoyl chloride (6). Yellow solid;
Yield: 64.7%; mp 146-147.degree. C.; MS (EI, 70 eV): m/z 317 (M);
.sup.1H-NMR (DMSO-d.sub.6, 200 MHz): .delta. 2.43 (s, 3H), 3.76 (s,
3H), 3.81 (s, 3H), 7.03-7.14 (m, 2H), 7.26-7.35 (m, 2H), 7.88-7.95
(m, 2H), 10.14 (s, 1H); .sup.13C-NMR (DMSO-d.sub.6, 50 MHz):
.delta. 31.76, 56.48, 61.38, 114.33, 115.83 (d, J=22 Hz), 121.91,
127.17, 130.65 (d, J=9.0 Hz), 131.06, 132.21, 145.90, 150.53,
164.57 (d, J=247 Hz), 164.94, 201.25; Anal. calcd for
C.sub.17H.sub.16FNO.sub.4: C, 64.35; H, 5.08; N, 4.41. Found: C,
64.36; H, 5.11; N, 4.40.
[0140] N-(2-Acetyl-3,4-methylenedioxyphenyl)-2-fluorobenzamide (10)
was obtained from 2 and 4. Yellow solid; Yield: 90.0%; mp
165-166.degree. C.; MS (EI, 70 eV): m/z 301 (M.sup.+); .sup.1H-NMR
(DMSO-d.sub.6, 200 MHz): .delta. 2.53 (s, 3H), 6.13 (s, 2H), 7.12
(d, J=8.6 Hz, 1H), 7.28-7.38 (m, 2H), 7.56-7.61 (m, 1H), 7.72-7.82
(m, 1H), 7.85 (d, J=8.8 Hz, 1H), 11.50 (s, 1H); .sup.13C-NMR
(DMSO-d.sub.6, 50 MHz): .delta. 32.53, 102.57, 111.92, 112.52,
114.74, 116.94 (d, J=22.5 Hz), 123.55 (d, J=12.5 Hz), 125.41,
130.98; 131.91, 134.04 (d, J=8.5 Hz), 144.46, 149.00, 157.18,
162.22, 199.61; Anal. calcd for C.sub.16H.sub.12FNO.sub.4: C,
63.79; H, 4.01; N, 4.65. Found: C, 63.75; H, 4.03; N, 4.67.
[0141] N-(2-Acetyl-3,4-methylenedioxyphenyl)-3-fluorobenzamide (11)
was obtained from 2 and 5. Yellow solid; Yield: 95.0%; mp
170-171.degree. C.; MS (EI, 70 eV): m/z 301 (M.sup.+); .sup.1H-NMR
(DMSO-d.sub.6. 200 MHz): .delta. 2.56 (s, 3H), 6.14 (s, 2H), 7.13
(d, J=8.4 Hz, 1H), 7.43 (t, J=8.6 Hz, 1H), 7.52-7.68 (m, 2H), 7.72
(d, J=8.6 Hz, 2H), 11.56 (s, 1H); .sup.13C-NMR (DMSO-d.sub.6, 50
MHz): .delta. 32.48, 102.61, 112.48, 112.62, 114.48 (d, J=23 Hz),
114.89, 119.30 (d, J=21.5 Hz), 123.56, 131.52 (d, J=8.0 Hz),
131.96, 137.32, 144.61, 148.88, 162.61 (d, J=243.5 Hz), 163.97,
199.88; Anal. calcd for C.sub.16H.sub.12FNO.sub.4: C, 63.79; H,
4.01; N, 4.65. Found: C, 63.67; H, 4.00; N, 4.63.
[0142] N-(2-Acetyl-3,4-methylenedioxyphenyl)-4-fluorobenzamide (12)
was obtained from 2 and 6. Yellow solid; Yield: 84.0%; mp
185-186.degree. C.; MS (EI, 70 eV): m/z 301 (M.sup.+); .sup.1H-NMR
(DMSO-d.sub.6. 200 MHz): .delta. 2.51 (s, 3H), 6.13 (s, 2H), 7.12
(d, J=8.6 Hz, 1H), 7.20-7.40 (m, 2H), 7.77 (d, J=8.6 Hz, 1H),
7.89-7.97 (m, 2H), 11.58 (s, 11-1); .sup.13C-NMR (DMSO-d.sub.6, 50
MHz): .delta. 32.55, 102.55, 111.20, 112.61, 114.54, 116.26 (d,
J=22 Hz), 130.22 (d, J=7.0 Hz), 131.47, 132.41, 144.36, 148.97,
162.22, 164.67 (d, J=248 Hz), 200.04; Anal. calcd for
C.sub.16H.sub.12FNO.sub.4: C, 63.79; H, 4.01; N, 4.65. Found: C,
63.84; H, 3.98; N, 4.65.
[0143] N-(2-Acetyl-5-benzyloxy-4-methoxyphenyl)-2-fluorobenzamide
(13) was obtained from 3 and 4. Yellow solid; Yield: 89.0%; mp
142-143.degree. C.; MS (EI, 70 eV): m/z 393 (M.sup.+); .sup.1H-NMR
(DMSO-d.sub.6. 200 MHz): .delta. 2.60 (s, 3H), 3.82 (s, 3H), 5.16
(s, 2H), 7.10-7.50 (m, 8H), 7.56-7.67 (m, 1H), 7.80-7.89 (m, 1H),
8.57 (s, 1H), 12.45 (d, J=4.0 Hz, 1H); .sup.13C-NMR (DMSO-d.sub.6,
50 MHz): .delta. 29.08, 56.42, 70.41, 105.31, 115.28, 116.05,
117.08 (d, J=22 Hz), 123.27 (d, J=12.5 Hz), 125.60, 128.58, 128.95,
131.20, 134.45 (d, J=8.5 Hz), 135.77, 136.50, 144.46, 152.98,
157.26, 162.35, 201.78; Anal. calcd for C.sub.23H.sub.20FNO.sub.4:
C, 70.22; H, 5.12; N, 3.56. Found: C, 70.18; H, 5.10; N, 3.55.
[0144] N-(2-Acetyl-5-benzyloxy-4-methoxyphenyl)-3-fluorobenzamide
(14) was obtained from 3 and 5. Yellow solid; Yield: 86.6%; mp
162-163.degree. C.; MS (EI, 70 eV): m/z 393 (M.sup.+); .sup.1H-NMR
(DMSO-d.sub.6, 200 MHz): .delta. 2.62 (s, 3H), 3.81 (s, 3H), 5.15
(s, 2H), 7.26-7.52 (m, 7H), 7.54-7.78 (m, 3H), 8.51 (s, 1H), 12.70
(s, 1H); .sup.13C-NMR (DMSO-d.sub.6, 50 MHz): .delta. 29.10, 56.42,
70.40, 104.74, 114.45, 115.29, 115.83, 119.59 (d, J=21.5 Hz),
123.36, 128.53, 128.95, 131.74 (d, J=7.5 Hz), 136.28, 136.45,
137.30 (d, J=6.5 Hz), 144.43, 153.26, 162.71 (d, J=244 Hz), 163.91,
202.48; Anal. calcd for C.sub.23H.sub.20FNO.sub.4: C, 70.22; H,
5.12; N, 3.56. Found: C, 70.20; H, 5.14; N, 3.52.
[0145] N-(2-Acetyl-5-benzyloxy-4-methoxyphenyl)-4-fluorobenzamide
(15) was obtained from 3 and 6. Yellow solid; yield: 67.1%; mp
168-169.degree. C.; MS (EI, 70 eV): m/z 393 (M.sup.+); .sup.1H-NMR
(DMSO-d.sub.6. 200 MHz): .delta. 2.63 (s, 3H), 3.81 (s, 3H), 5.15
(s, 2H), 7.2-7.5 (m, 7H), 7.9-8.1 (m, 3H), 8.54 (s, 1H), 12.69 (s,
1H); .sup.13C-NMR (DMSO-d.sub.6, 50 MHz): .delta. 29.11, 56.47,
70.41, 104.73, 115.39, 115.83, 116.27, 116.72, 128.53, 128.94,
130.17 (d, J=9.0 Hz), 132.54 (d, J=9.5 Hz), 136.48, 136.58, 144.33,
153.33, 164.24, 166.82, 202.48; Anal. calcd for
C.sub.23H.sub.20FNO.sub.4: C, 70.22; H, 5.12; N, 3.56. Found: C,
70.24; H, 5.12; N, 3.59.
[0146] 2-(2-Fluorophenyl)-5,6-dimethoxyquinolin-4-one (16). To a
suspension of 7 (0.50 g, 1.58 mmol) in t-butyl alcohol (30 mL) was
added potassium t-butoxide (1.0 g, 8.93 mmol). The mixture was
refluxed under argon for 20 h and evaporated. The residue was
treated with a 10% ammonium chloride solution (30 mL). The solid
precipitate was collected and washed with n-hexane and Me.sub.2CO.
The crude product was recrystallized from MeOH afforded yellow
needle of 16 (0.27 g, 0.9 mmol). Yield: 57.1%; mp 215-217.degree.
C.; MS (EI, 70 eV): m/z 299 (M.sup.+); IR (KBr): 1628 (C.dbd.O)
cm.sup.-1; .sup.1H-NMR (DMSO-d.sub.6. 200 MHz): .delta. 3.72 (s,
3.81 (s, 3H), 6.06 (s, 1H), 7.3-7.6 (m, 5H), 7.60-7.71 (m, 1H);
Anal. calcd for C.sub.17H.sub.14FNO.sub.3: C, 68.22; H, 4.71; N,
4.68. Found: C, 68.24; H, 4.67; N, 4.71.
[0147] 2-(3-Fluorophenyl)-5,6-dimethoxyquinolin-4-one (17) was
obtained from 8. Yellow needle; yield: 53.1%; mp 190-192.degree.
C.; MS (EI, 70 eV): m/z 299 (M.sup.+); IR (KBr): 1599 (C.dbd.O)
cm.sup.-1; .sup.1H-NMR (DMSO-d.sub.6.200 MHz): .delta. 3.73 (s,
3H), 3.81 (s, 3H), 6.35 (s, 1H), 7.28-7.40 (m, 1H), 7.46-7.60 (m,
3H), 7.64-7.76 (m, 2H); Anal. calcd for C.sub.17H.sub.14FNO.sub.3:
C, 68.22; H, 4.71; N, 4.68. Found: C, 68.17; H, 4.68; N, 4.66.
[0148] 2-(4-Fluorophenyl)-5,6-dimethoxyquinolin-4-one (18) was
obtained from 9. White needle; yield: 54.6%; mp 227-229.degree. C.;
MS (EI, 70 eV): m/z 299 (M.sup.+); IR (KBr): 1607 (C.dbd.O)
cm.sup.-1; .sup.1H-NMR (DMSO-d.sub.6,200 MHz): .delta. 3.72 (s,
3H), 3.80 (s, 3H), 6.26 (s, 1H), 7.31-7.40 (m, 2H), 7.44-7.54 (m,
2H), 7.83-7.90 (m, 2H); Anal. calcd for C.sub.17H.sub.14FNO.sub.3:
C, 68.22; H, 4.71; N, 4.68. Found: C, 68.16; H, 4.68; N, 4.65.
[0149] 2-(2-Fluorophenyl)-5,6-methylenedioxyquinolin-4-one (19) was
obtained from 10. Yellow solid; yield: 47.6%; mp 282-283.degree.
C.; MS (EI, 70 eV): m/z 283 (M.sup.+); IR (KBr): 1605 (C.dbd.O)
cm.sup.-1; .sup.1H-NMR (DMSO-d.sub.6, 200 MHz): .delta. 5.92 (s,
1H), 6.11 (s, 2H), 7.09 (d, J=8.8 Hz, 1H), 7.27-7.38 (m, 3H),
7.55-7.70 (m, 2H), 11.71 (s, 1H); Anal. calcd for
C.sub.16H.sub.10FNO.sub.3: C, 67.84; H, 3.56; N, 4.94. Found: C,
67.82; H, 3.53; N, 4.91.
[0150] 2-(3-Fluorophenyl)-5,6-methylenedioxyquinolin-4-one (20) was
obtained from 11. White solid; yield: 44.9%; mp 286-288.degree. C.;
MS (EI, 70 eV): m/z 283 (M.sup.+); IR (KBr): 1609 (C.dbd.O)
cm.sup.-1; .sup.1H-NMR (DMSO-d.sub.6, 200 MHz): .delta. 6.11 (s,
2H), 6.19 (s, 1H), 7.19-7.36 (m, 3H), 7.55-7.67 (m, 3H), 11.71 (s,
1H); Anal. calcd for C.sub.16H.sub.10FNO.sub.3: C, 67.84; H, 3.56;
N, 4.94. Found: C, 67.90; H, 3.52; N, 4.95.
[0151] 2-(4-Fluorophenyl)-5,6-methylenedioxyquinolin-4-one (21) was
obtained from 12. White solid; yield: 45.9%; mp 286-288.degree. C.;
MS (EI, 70 eV): m/z 283 (M.sup.+); IR (KBr): 1613 (C.dbd.O)
cm.sup.-1; .sup.1H-NMR (DMSO-d.sub.6, 200 MHz): .delta. 6.10 (s,
3H), 7.17-7.31 (m, 2H), 7.32-7.41 (m, 2H), 7.78-7.85 (m, 2H), 11.46
(s, 1H); Anal. calcd for C.sub.16H.sub.10FNO.sub.3: C, 67.84; H,
3.56; N, 4.94. Found: C, 67.88; H, 3.51; N, 4.97.
[0152] 7-Benzyloxy-2-(2-fluorophenyl)-6-methoxyquinolin-4-one (22)
was obtained from 13. White solid; yield: 60.5%; mp 132-134.degree.
C.; MS (EI, 70 eV): m/z 375 (M.sup.+); .sup.1H-NMR (DMSO-d.sub.6,
200 MHz): .delta. 3.82 (s, 3H), 5.16 (s, 2H), 6.21 (s, 1H),
7.20-7.80 (m, 11H); .sup.13C-NMR (DMSO-d.sub.6, 50 MHz): .delta.
56.02, 70.40, 101.86, 104.14, 108.80, 116.77 (d, J=21.5 Hz),
118.86, 123.30 (d, J=13 Hz), 125.43, 128.50, 128.97, 131.24, 132.56
(d, J=8.0 Hz), 136.58, 137.08, 144.73, 147.73, 152.52, 159.64 (d,
J=247 Hz), 174.57; Anal. calcd for C.sub.23H.sub.18FNO.sub.3: C,
73.59; H, 4.83; N, 3.73. Found: C, 73.55; H, 4.81; N, 3.71.
[0153] 7-Benzyloxy-2-(3-fluorophenyl)-6-methoxyquinolin-4-one (23)
was obtained from 14. White solid; yield: 64.3%; mp 154-155.degree.
C.; MS (EI, 70 eV): m/z 375 (M.sup.+); .sup.1H-NMR (DMSO-d.sub.6,
200 MHz): .delta. 3.83 (s, 3H), 5.17 (s, 2H), 6.56 (s, 1H),
7.30-7.50 (m, 8H), 7.55-7.60 (m, 1H), 7.60-7.80 (m, 2H);
.sup.13C-NMR (DMSO-d.sub.6, 50 MHz): .delta. 56.07, 70.45, 102.27,
103.72, 106.03, 114.71 (d, J=23.5 Hz), 117.56 (d, J=20.5 Hz),
118.44, 123.95, 128.56, 128.99, 131.50, 136.49, 137.41, 148.02,
148.44, 152.72, 165.13, 173.61; Anal. calcd for
C.sub.23H.sub.18FNO.sub.3: C, 73.59; H, 4.83; N, 3.73. Found: C,
73.61; H, 4.80; N, 3.72.
[0154] 7-Benzyloxy-2-(4-fluorophenyl)-6-methoxyquinolin-4-one (24)
was obtained from 15. White solid; yield: 64.4%; mp 248-249.degree.
C.; MS (EI, 70 eV): m/z 375 (M.sup.+); .sup.1H-NMR
(DMSO-d.sub.6.200 MHz): .delta. 3.80 (s, 3H), 5.13 (s, 2H), 6.26
(s, 1H), 7.20-7.60 (m, 9H), 7.80-8.00 (m, 2H); .sup.13C-NMR
(DMSO-d.sub.6, 50 MHz): .delta. 55.96, 70.36, 101.41, 104.51,
106.61, 116.30 (d, J=21.5 Hz), 119.27, 128.56, 128.99, 130.05 (d,
J=8.0 Hz), 136.60, 147.39, 148.06, 152.19, 163.63 (d, J=246.5 Hz),
176.10; Anal. calcd for C.sub.23H.sub.18FNO.sub.3: C, 73.59; H,
4.83; N, 3.73. Found: C, 73.56; H, 4.83; N, 3.75.
[0155] 2,3-Dimethoxyacetophenone (26). To a stirred solution of
2,3-dimethoxybenzonitrile (25)(5.0 g, 30 mmol) in Et.sub.2O (12.5
mL) under N.sub.2 atmosphere was added methylmagnesium bromide (37%
in Et.sub.2O) (12.5 mL, 37 mmol). The mixture was stirred for 16 h,
and then 50% AcOH (20 mL) was added. After it was stirred for 30
min, the solution was poured into crushed ice, extracted with
CH.sub.2Cl.sub.2, washed with 10% Na.sub.2CO.sub.3 and then with
water, dried over MgSO.sub.4 and concentrated. The crude was
purified by column chromatography (SiO.sub.2, n-hexane: EtOAc=4:1)
to give 26. Liquid; yield: 92.5%; .sup.1H-NMR (CDCl.sub.3, 200
MHz): .delta. 2.56 (s, 3H), 3.82 (s, 3H), 3.85 (s, 3H), 6.99-7.02
(m, 2H), 7.13-7.18 (m, 1H); .sup.13C-NMR (CDCl.sub.3, 50 MHz):
.delta. 31.18, 55.98, 61.29, 115.83, 120.80, 123.94, 133.62,
148.63, 153.04, 200.26; Anal. calcd for C.sub.10H.sub.12O.sub.3: C,
66.65; H, 6.71. Found: C, 66.60; H, 6.73.
[0156] 6-Amino-2,3-dimethoxyacetophenone (1). Compound 26 (5.0 g,
27.8 mmol) was stirred at -5.+-.1.degree. C. and 70% HNO.sub.3 (60
mL) was added dropwise. After it was stirred at -5.+-.1.degree. C.
for 10 min, the reaction mixture was poured into crushed ice,
extracted with CH.sub.2Cl.sub.2. The extract was washed with 10%
Na.sub.2CO.sub.3 and then with water, dried over MgSO.sub.4 and
concentrated. The crud intermediate (27) was directly in the next
step.
[0157] A solution of 27 (1.85 g, 8.22 mmol) in anhydrous MeOH (40
mL) was hydrogenated in the presence of 10% Pd/C (0.5 g) at
25.+-.2.degree. C. for 2 h. The Pd/C was filtered off and the
filtrate was evaporated. The residue was purified by column
chromatography (SiO.sub.2, n-hexane: EtOAc=25:1) to give 1. Liquid;
yield: 43.7%; .sup.1H-NMR (DMSO-d.sub.6, 200 MHz): .delta. 2.41 (s,
3H), 3.66 (s, 3H), 3.74 (s, 3H), 5.88 (s, 2H), 6.41 (d, J=9.0 Hz,
1H), 6.98 (d, J=9.0 Hz, 1H); .sup.13C-NMR (DMSO-d.sub.6, 50 MHz):
.delta. 33.09, 57.58, 61.14, 111.82, 116.82, 121.15, 142.62,
144.22, 149.87, 201.88; Anal. calcd for C.sub.10H.sub.13NO.sub.3:
C, 61.53; H, 6.71; N, 7.18. Found: C, 61.51; H, 6.74; N, 7.22.
[0158] 2,3-Dihydroxyacetophenone (30). To a solution of
1,2-dihydroxybenzene (28)(2.0 g, 18.2 mmol) in AcOH (1.3 g, 21.7
mmol) was added boron trifluoride diethyl ether (98% in Et.sub.2O,
2 mL). The mixture was reacted under microwave irradiation (300 W)
for 1.5 min and then cooled to 25.degree. C. The reaction mixture
was dissolved in dichoromethane (10 mL) and H.sub.2O (about 20 mL).
The organic lay was washed with 10% NaHCO.sub.3 and then with
water, dried over MgSO.sub.4 and concentrated. The crude was
purified by column chromatography (SiO.sub.2, CH.sub.2Cl.sub.2) to
give 30. Yellow solid; yield: 10.4%; mp 76-77.degree. C.;
.sup.1H-NMR (CDCl.sub.3,200 MHz): .delta. 2.58 (s, 3H), 5.79 (s,
1H), 6.79 (t, J=8.0 Hz, 1H), 7.10 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.0
Hz, 1H), 12.45 (s, 1H); .sup.13C-NMR (CDCl.sub.3, 50 MHz): .delta.
26.73, 118.79, 119.52, 120.39, 121.44, 145.40, 149.50, 205.08;
Anal. calcd for C.sub.8H.sub.8O.sub.3: C, 63.15; H, 5.30. Found: C,
63.10; H, 5.33.
[0159] 2,3-Methylenedioxyacetophenone (31). To a suspension of
K.sub.2CO.sub.3 (1.24 g, 9.0 mmol) in DMF (10 mL) was added
diiodomethane (2.4 g, 9.0 mmol). The mixture was heated to
100-110.degree. C. and added a solution of 15 (1.0 g, 6.6 mmol) in
DMF (5 mL) dropwise. The reaction mixture was stirred at
110.degree. C. for 1 h and poured into crushed ice, extracted with
CH.sub.2Cl.sub.2. The extract was washed with brine, dried over
MgSO.sub.4 and evaporated. The crude was purified by column
chromatography (SiO.sub.2, n-hexane: EtOAc=4:1) to give 31. White
solid; yield: 61.0%; mp 89-91.degree. C.; .sup.1H-NMR (CDCl.sub.3.
200 MHz): .delta. 2.58 (s, 3H), 6.07 (s, 2H), 6.87 (q, J=7.8 Hz,
1H), 6.95 (dd, J=8.0, 1.5 Hz, 1H), 7.35 (dd, J=8.0, 1.5 Hz, 1H);
.sup.13C-NMR (CDCl.sub.3, 50 MHz): .delta. 30.29, 101.58, 112.51,
120.27, 121.25, 121.43, 148.00, 148.60, 195.58; Anal. calcd for
C.sub.9H.sub.8O.sub.3: C, 65.85; H, 4.91. Found: C, 65.75; H,
4.93.
[0160] 6-Amino-2,3-methylenedioxyacetophenone (2). Compound 31
(0.63 g, 3.7 mmol) was allowed to react in the same manner as
described in the preparation of compound 1 to give compound 2.
Yellow solid; yield: 48.2%; mp 102-104.degree. C.; .sup.1H-NMR
(DMSO-d.sub.6.200 MHz): .delta. 2.44 (s, 3H), 5.92 (s, 2H), 6.14
(d, J=8.6 liz, 1H), 6.72 (s, 2H), 6.89 (d, J=8.6 Hz, 1H);
.sup.13C-NMR (DMSO-d.sub.6, 50 MHz): .delta. 32.63, 101.08, 105.44,
107.71, 115.75, 136.77, 146.80, 148.78, 198.02; Anal. calcd for
C.sub.9H.sub.9NO.sub.3: C, 60.33; H, 5.06; N, 7.82. Found: C,
60.31; H, 5.09; N, 7.83.
[0161] 4-Benzyloxy-3-methoxyacetophenone (35). To a solution of
acetovanillone (33) (4.70 g, 28.3 mmol) in MeCN (60 mL) was added
K.sub.2CO.sub.3 (8.05 g, 58.3 mmol) and KI (0.20 g, 1.2 mmol). The
mixture was stirred under N.sub.2 atmosphere and benzyl bromide
(34) (4.0 mL, 34 mmol) was added dropwise. The reaction mixture was
reflux for 24 h and then cooled to 25.degree. C., then resulting
precipitate was filtered off. The filtrate was evaporated and
purified by column chromatography (SiO.sub.2, n-hexane:
CH.sub.2Cl.sub.2=1:2) to give 30. White solid; yield: 70.3%; mp
87-88.degree. C.; .sup.1H-NMR (CDCl.sub.3. 200 MHz): .delta. 2.51
(s, 3H), 3.91 (s, 3H), 5.20 (s, 2H), 6.86 (d, J=8.2 Hz, 1H),
7.21-7.55 (m, 7H); .sup.13C-NMR (CDCl.sub.3, 50 MHz): .delta.
26.19, 56.05, 70.79, 110.53, 112.13, 123.07, 127.18, 128.10,
128.68, 130.72, 136.28, 149.49, 152.41, 196.80; Anal. calcd for
C.sub.16H.sub.16O.sub.3: C, 74.98; H, 6.29. Found: C, 75.02; H,
6.25.
[0162] 4-Benzyloxy-3-methoxy-6-nitroacetophenone (36). To a
solution of 35 (1.24 g, 4.83 mmol) in AcOH (15 mL) was added f.
HNO.sub.3 (1.5 mL, 36 mmol) dropwise at 0.degree..+-.1.degree. C.
The mixture was stirred at 25.degree. C. for 24 h and then poured
into crushed ice. The precipitate was collected and washed with
H.sub.2O. The crude was purified by column chromatography
(SiO.sub.2, n-hexane: EtOAc=2:1) to give 36. Yellow solid; yield:
68.8%; mp 142-143.degree. C.; .sup.1H-NMR (CDCl.sub.3. 200 MHz):
.delta. 2.46 (s, 3H), 3.95 (s, 3H), 5.19 (s, 2H), 6.74 (s, 1H),
7.30-7.48 (m, 5H), 7.64 (s, 1H); .sup.13C-NMR (CDCl.sub.3, 50 MHz):
.delta. 30.41, 56.67, 71.39, 108.78, 127.56, 128.56, 128.84,
133.08, 135.19, 138.21, 148.54, 154.53, 200.13; Anal. calcd for
C.sub.16H.sub.15NO.sub.5: C, 63.78; H, 5.02; N, 4.65. Found: C,
63.82; H, 5.00; N, 4.63.
[0163] 2-Amino-4-benzyloxy-5-methoxyacetophenone (3). To a solution
of 36 (1.0 g, 3.32 mmol) in anhydrous EtOH (100 mL) was added Tin
chloride dihydrate (3.7 g, 16.4 mmol). The mixture was reflux for 2
h and then cooled to 25.degree. C., and poured in 5% NaHCO.sub.3
solution. The precipitate was collected and washed with H.sub.2O
and then extracted with EtOAc. The extract was wash with H.sub.2O,
dried over MgSO.sub.4 and evaporated. The crude was purified by
column chromatography (SiO.sub.2, n-hexane: EtOAc=1:1) to give 7c.
Yellow solid; yield: 72.2%; mp 135-137.degree. C.; .sup.1H-NMR
(DMSO-d.sub.6.200 MHz): .delta. 2.39 (s, 3H), 3.66 (s, 3H), 5.03
(s, 2H), 6.38 (s, 1H), 7.05 (s, 2H), 7.10 (s, 1H), 7.30-7.50 (m,
5H); .sup.13C-NMR (DMSO-d.sub.6, 50 MHz): .delta. 28.21, 56.94,
69.87, 100.05, 109.70, 115.40, 128.34, 128.49, 128.93, 136.83,
139.45, 148.74, 154.64, 198.06; Anal. calcd for
C.sub.16H.sub.17NO.sub.3: C, 70.83; H, 6.32; N, 5.16. Found: C,
70.82; H, 6.30; N, 5.20.
[0164] 2-(2-Fluorophenyl)-5-hydroxy-6-methoxyquinolin-4-one (37).
To a solution of 16 (0.2 g, 0.67 mmol) in CH.sub.2Cl.sub.2 (3 mL)
was added 5 mL of BCl.sub.3 solution (1 M in CH.sub.2Cl.sub.2)
dropwise at 0.degree..+-.1.degree. C. The mixture was stirred at
25.+-.1.degree. C. for 2 h and then poured into crushed ice,
extracted with EtOAc. The organic layer was washed with H.sub.2O,
dried over MgSO.sub.4 and evaporated. The crude was purified by
column chromatography (SiO.sub.2, CHCl.sub.3: MeOH=15:1) and
recrystallized from MeOH to give 37. Yellow solid; yield: 24.1%; mp
268-270.degree. C.; MS (EI, 70 eV): m/z 285 (M.sup.+); IR (KBr):
1604.77 (C.dbd.O) cm.sup.-1; .sup.1H-NMR (DMSO-d.sub.6. 200 MHz):
.delta. 3.78 (s, 3H), 6.11 (s, 1H), 7.01 (d, J=7.4 Hz, 1H),
7.36-7.48 (m, 3H), 7.54-7.72 (m, 2H), 12.25 (s, 1H), 14.54 (s, 1H);
.sup.13C-NMR (DMSO-d.sub.6, 50 MHz): .delta. 55.80, 106.22, 106.43,
112.88, 116.36 (d, J=23 Hz), 120.81, 121.96 (d, J=13.5 Hz), 125.04,
130.85, 132.67 (d, J=8.6 Hz), 135.09, 141.02, 146.27, 149.29,
158.92 (d, J=247.7 Hz), 181.97; Anal. calcd for
C.sub.16H.sub.12FNO.sub.3: C, 67.36; H, 4.24; N, 4.91. Found: C,
67.32; H, 4.26; N, 4.89.
[0165] 2-(3-Fluorophenyl)-5-hydroxy-6-methoxyquinolin-4-one (38)
was obtained from 17 and BCl.sub.3. Yellow solid; yield: 26.7%; mp
274-276.degree. C.; MS (EI, 70 eV): m z 285 (M.sup.+); IR (KBr):
1606.70 (C.dbd.O) cm.sup.-1; .sup.1H-NMR (DMSO-d.sub.6, 200 MHz):
.delta. 3.77 (s, 3H), 6.33 (s, 1H), 7.11 (d, J=8.8 Hz, 1H),
7.33-7.48 (m, 2H), 7.51-7.76 (m, 3H), 12.09 (s, 1H), 14.56 (s, 1H);
.sup.13C-NMR (DMSO-d.sub.6, 50 MHz): .delta. 57.19, 104.82, 106.97,
113.39, 115.09 (d, J=23 Hz), 118.06 (d, J=21 Hz), 121.07, 124.32,
131.64 (d, J=9.0 Hz), 135.61, 136.16 (d, J=8.0 Hz), 141.49, 149.64,
150.12, 162.64 (d, J=242.5 Hz), 182.69; Anal, calcd for
C.sub.16H.sub.12FNO.sub.3: C, 67.36; H, 4.24; N, 4.91. Found: C,
67.35; H, 4.24; N, 4.92.
[0166] 2-(4-Fluorophenyl)-5-hydroxy-6-methoxyquinolin-4-one (39)
was obtained from 18 and BCl.sub.3. Yellow solid; yield: 23.0%; mp
307-309.degree. C.; MS (EI, 70 eV): m/z 285 (M.sup.+); IR (KBr):
1610.56 (C.dbd.O) cm.sup.-1; .sup.1H-NMR (DMSO-d.sub.6, 200 MHz):
.delta. 3.76 (s, 3H), 6.25 (s, 1H), 7.08 (d, J=9.0 Hz, 1H),
7.34-7.43 (m, 3H), 7.82-7.89 (m, 2H), 12.01 (s, 1H), 14.60 (s, 1H);
.sup.13C-NMR (DMSO-d.sub.6, 50 MHz): .delta. 57.19, 104.53, 106.84,
113.23, 116.47 (d, J=22 Hz), 120.99, 130.55 (d, J=9.0 Hz), 135.62,
141.45, 149.69, 150.64, 164.02 (d, J=247 Hz), 182.59; Anal. calcd
for C.sub.16H.sub.12FNO.sub.3: C, 67.36; H, 4.24; N, 4.91. Found:
C, 67.36; H, 4.24; N, 4.92.
[0167] 2-(2-Fluorophenyl)-5,6-dihydroxyquinolin-4-one (40). To a
solution of 19 (0.1 g, 0.35 mmol) in anhydrous MeOH (30 mL) was
hydrogenated in the presence of 10% Pd/C (0.2 g) at 25.+-.2.degree.
C. for 40 h. The catalyst was filtered off and the filtrate was
evaporated. The crude was purified by column chromatography
(SiO.sub.2, EtOAc: MeOH=30:1) to give 40. White solid; yield:
13.7%; mp 152-154.degree. C.; MS (EI, 70 eV): m/z 271 (M.sup.+); IR
(KBr): 1622.13 (C.dbd.O) cm.sup.-1; .sup.1H-NMR (DMSO-d.sub.6, 200
MHz): .delta. 6.03 (s, 1H), 7.15 (d, J=8.8 Hz, 1H), 7.30-7.70 (m,
6H), 9.72 (s, 1H), 11.76 (s, 1H); .sup.13C-NMR (DMSO-d.sub.6, 50
MHz): .delta. 107.67, 108.57, 116.75 (d, J=21.5 Hz), 120.54,
122.67, 123.36, 125.42, 126.70, 131.22, 132.49, 134.35, 144.30,
154.29, 159.43 (d, J=248.5 Hz), 176.82; Anal. calcd for
C.sub.15H.sub.10FNO.sub.3: C, 66.42; H, 3.72; N, 5.16. Found: C,
66.38; H, 3.70; N, 5.15.
[0168] 2-(3-Fluorophenyl)-5,6-dihydroxyquinolin-4-one (41) was
obtained from 20. White solid; yield: 15.0%; mp 307-308.degree. C.;
MS (EI, 70 eV): m/z 271 (M.sup.+); IR (KBr): 1608.63 (C.dbd.O)
cm.sup.-1; .sup.1H-NMR (DMSO-d.sub.6 200 MHz): .delta. 6.25 (s,
1H), 7.15 (d, J=8.8 Hz, 1H), 7.30-7.50 (m, 2H), 7.50-7.80 (m, 4H),
9.72 (s, 1H), 11.60 (s, 1H); .sup.13C-NMR (DMSO-d.sub.6, 50 MHz):
.delta. 106.38, 107.57, 114.65 (d, J=23 Hz), 117.38 (d, J=21.5 Hz),
120.91, 122.62, 123.91, 126.81, 131.52 (d, J=8.5 Hz), 134.45,
137.17, 147.66, 154.36, 162.70 (d, J=242 Hz), 176.82; Anal. calcd
for C.sub.15H.sub.10FNO.sub.3: C, 66.42; H, 3.72; N, 5.16. Found:
C, 66.43; H, 3.74; N, 5.13.
[0169] 2-(4-Fluorophenyl)-5,6-dihydroxyquinolin-4-one (42) was
obtained from 21. White solid; yield: 13.9%; mp 332-334.degree. C.;
MS (EI, 70 eV): m/z 271 (M.sup.+); IR (KBr): 1614.42 (C.dbd.O)
cm.sup.-1; .sup.1H-NMR (DMSO-d.sub.6, 200 MHz): .delta. 6.18 (s,
1H), 7.14 (dd, J=9.0, 2.8 Hz, 1H), 7.33-7.42 (m, 3H), 7.59 (d,
J=8.8 Hz, 1H), 7.79-7.86 (m, 2H), 9.70 (s, 1H), 11.59 (s, 1H);
.sup.13C-NMR (DMSO-d.sub.6, 50 MHz): .delta. 106.24, 107.68, 116.39
(d, J=21.5 Hz), 120.71, 122.48, 126.73, 130.19 (d, J=8.5 Hz),
131.38, 134.42, 148.24, 154.20, 163.70 (d, J=247.5 Hz), 176.81;
Anal. calcd for C.sub.15H.sub.10FNO.sub.3: C, 66.42; H, 3.72; N,
5.16. Found: C, 66.47; H, 3.69; N, 5.14.
[0170] 2-(2-Fluorophenyl)-7-hydroxy-6-methoxyquinolin-4-one (43).
Compound 22 (0.3 g, 0.80 mmol) was allowed to react in the same
manner as described in the preparation of compound 40 to give 43.
White solid; yield: 61.3%; mp 277-279.degree. C.; MS (EI, 70 eV):
m/z 285 (M.sup.+); IR (KBr): 1622.13 (C.dbd.O) cm.sup.-1;
.sup.1H-NMR (DMSO-d.sub.6 200 MHz): .delta. 3.82 (s, 3H), 6.04 (s,
1H), 7.01 (s, 1H), 7.32-7.50 (m, 3H), 7.50-7.67 (m, 2H), 10.22 (s,
1H), 11.68 (s, 1H); .sup.13C-NMR (DMSO-d.sub.6, 50 MHz): .delta.
55.52, 102.72, 105.37, 108.20, 116.28 (d, J=22.5 Hz), 118.07,
122.94, 124.92, 130.75, 131.99 (d, J=7.95 Hz), 136.45, 143.61,
146.58, 151.59, 158.98 (d, J=246.9 Hz), 175.30; Anal. calcd for
C.sub.16H.sub.12FNO.sub.3: C, 67.36; H, 4.24; N, 4.91. Found: C,
67.37; H, 4.26; N, 4.90.
[0171] 2-(3-Fluorophenyl)-7-hydroxy-6-methoxyquinolin-4-one (44)
was obtained from 23. White solid; yield: 44.8%; mp 326-328.degree.
C.; MS (EI, 70 eV): m/z 285 (M.sup.+); IR (KBr): 1606.70 (C.dbd.O)
cm.sup.-1; .sup.1H-NMR (DMSO-d.sub.6, 200 MHz): .delta. 3.81 (s,
3H), 6.24 (s, 1H), 7.12 (s, 1H), 7.27-7.42 (m, 2H), 7.47-7.70 (m,
3H), 10.20 (s, 1H), 11.44 (s, 1H); .sup.13C-NMR (DMSO-d.sub.6, 50
MHz): .delta. 55.92, 103.35, 104.70, 106.67, 114.59 (d, J=23 Hz),
117.26 (d, J=21 Hz), 118.85, 123.85, 131.47 (d, J=8.0 Hz), 136.85,
137.16, 146.94, 147.33, 151.93, 162.69 (d, J=242.5 Hz), 176.37;
Anal. calcd for C.sub.16H.sub.12FNO.sub.3: C, 67.36; H, 4.24; N,
4.91. Found: C, 67.32; 1-1, 4.22; N, 4.93.
[0172] 2-(4-Fluorophenyl)-7-hydroxy-6-methoxyquinolin-4-one (45)
was obtained from 24. White solid; yield: 42.5%; mp 352-354.degree.
C.; MS (EI, 70 eV): m/z 285 (M.sup.+); IR (KBr): 1610.56 (C.dbd.O)
cm.sup.-1; .sup.1H-NMR (DMSO-d.sub.6, 200 MHz): .delta. 3.80 (s,
3H), 6.19 (s, 1H), 7.11 (s, 1H), 7.20-7.50 (m, 3H), 7.70-7.90 (m,
2H); .sup.13C-NMR (DMSO-d.sub.6, 50 MHz): .delta. 55.89, 103.50,
104.55, 106.18, 116.30 (d, J=21.5 Hz), 118.41, 130.03 (d, J=8.5
Hz), 131.57, 137.22, 147.00, 148.01, 152.21, 163.58 (d, J=246 Hz),
175.93; Anal. calcd for C.sub.16H.sub.12FNO.sub.3: C, 67.36; H,
4.24; N, 4.91. Found: C, 67.39; H, 4.20; N, 4.89.
2-(3-Fluorophenyl)-6-methoxyquinoline-4,5-diyl bis(dibenzyl
phosphate) (48)
[0173] Method A: To a stirred solution of 38 (0.12 g, 0.42 mmol) in
dry THF (20 mL) was added NaH (96 mg, 4 mmol) at
0.degree..+-.1.degree. C. After it was stirred for 1 h, tetrabenzyl
pyrophosphate (46) (430 mg, 0.8 mmol) was added and stirring was
continued for 25 min. The reaction mixture was filtered and washed
with CH.sub.2Cl.sub.2. The filtrate was concentrated under vacuum
at a temperature below 30.degree. C. The residue was purified by
column chromatography (SiO.sub.2, n-hexane: EtOAc) to give 48.
Liquid; yield: 95.0%; Method B: To a stirred solution of 38 (1.85
g, 6.5 mmol) in acetonitrile (50 mL) was added CCl.sub.4 (10 eq.)
at -10.degree. C. N,N-diisopropylethylamine (DIPEA)(4.2 eq.)
followed by N,N-dimethylaminopyridine (DMAP)(0.2 eq.) were added.
One minute later, dropwise addition of dibenzyl phosphate (47) was
begun. When the reaction was complete as determined by TLC, 0.5 M
aqueous KH.sub.2PO.sub.4 was added and the mixture was allowed to
warm to room temperature and extracted with EtOAc. The organic
layer was washed with H.sub.2O, dried over MgSO.sub.4 and
evaporated. The crude was purified by column chromatography (EA:
n-hex=1:1) to give 48. Liquid; yield: 96.0%. Compound 48: MS (EI,
70 eV): m/z 805 (M.sup.+); .sup.1H-NMR (DMSO-d.sub.6, 200 MHz):
.delta. 3.87 (s, 3H), 5.10 (s, 2H), 5.14 (s, 2H), 5.18 (s, 2H),
5.22 (s, 2H), 7.20-7.36 (m, 21H), 7.47-7.60 (m, 1H), 7.72-7.84 (m,
4H), 8.01 (d, J=9.4 Hz, 1H); .sup.13C-NMR (DMSO-d.sub.6, 50 MHz):
.delta. 57.27, 69.63, 69.74, 70.12, 70.23, 110.20, 113.57, 114.03,
116.23, 116.92, 117.35, 119.48, 123.28, 128.10, 128.38, 128.70,
128.79, 128.85, 128.95, 131.35, 131.51, 135.79, 135.94, 136.32,
136.47, 140.41, 140.56, 145.39, 149.74, 149.82, 153.44, 153.57,
153.92, 160.71, 165.56; Anal. (C.sub.44H.sub.38FNO.sub.9P.sub.2) C,
H, N.
[0174] 2-(3-Fluorophenyl)-6-methoxyquinoline-4,5-diyl
bis(dihydrogen phosphate) (49). A suspension of 48 (153 mg, 0.19
mmol) in anhydrous MeOH (10 mL) was hydrogenated in the presence of
10% Pd/C (80 mg) at 25.degree. C. for 15 min. The catalyst and
precipitate were collected and dissolved in 10% NaHCO.sub.3
solution and then filtered. The filtrate was acidified with dil aq
HCl and the precipitate was then collected and washed with acetone
to give 49. Yellow solid; yield: 87%; mp>300.degree. C.; MS
(ESI): m/z 444 (M-H).sup.-; .sup.1H-NMR (D.sub.2O, 200 MHz):
.delta. 3.85 (s, 3H), 7.29 (t, J=8.0 Hz, 1H), 7.43-7.68 (m, 4H),
7.72-7.92 (m, 2H); Anal. (C.sub.16H.sub.14FNO.sub.9P.sub.2) C, H,
N.
[0175] 2-(3-Fluorophenyl)-6-methoxyquinoline-4,5-diyl bis(disodium
phosphate) (50). To a stirred solution of NaHCO.sub.3 (0.67 g, 8.0
mmol) in H.sub.2O (20 mL) was added 49 (0.89 g, 2.0 mmol) at
0.degree..+-.1.degree. C. After the addition was complete, the
reaction mixture was removed from the ice bath, stirred at
25.degree. C. for 10 min and the filtered though celite, after no
dissolution from the solid was observed. The resulting filtrate (15
mL) was poured into acetone (60 mL), and kept it in an ice bath for
1 h. The precipitate was collected and washed with ice-cooled
acetone (10 mL.times.5). The solid was dried under vacuum to give
50. White solid; yield: 52.3%; mp>300.degree. C.; MS (ESI): m/z
534 (M+H).sup.+; .sup.1H-NMR (D.sub.2O, 200 MHz): .delta. 3.81 (s,
3H), 7.10 (t, J=8.2 Hz, 1H), 7.34-7.52 (m, 2H), 7.60-7.72 (m, 4H);
Anal. (C.sub.16H.sub.10FNNa.sub.4O.sub.9P.sub.2) C, H, N.
[0176] Dibenzyl
2-(3-fluorophenyl)-6-methoxy-4-oxo-1,4-dihydroquinolin-5-yl
phosphate (51). A suspension of 48 (2.42 mg, 3.0 mmol) in anhydrous
MeOH (10 mL) was stirred at 25.degree. C. for 24 h. The reaction
mixture was concentrated under vacuum at a temperature below
30.degree. C. The residue was purified by column chromatography
(SiO.sub.2, n-hexane: EtOAc) to give 51. Yellow solid; yield:
80.0%; mp 136-138.degree. C.; MS (ESI): m/z 544.5 (M-H).sup.-;
.sup.1H-NMR (DMSO-d.sub.6, 200 MHz): .delta. 3.75 (s, 3H), 5.28 (s,
2H), 5.31 (s, 2H), 6.27 (s, 1H), 7.26-7.50 (m, 11H), 7.50-7.78 (m,
6H); .sup.13C-NMR (DMSO-d.sub.6, 50 MHz): .delta. 57.19, 69.32,
69.44, 108.51, 114.46, 114.93, 116.74, 117.38, 119.24, 123.92,
128.04, 128.51, 128.82, 131.49, 131.65, 136.74, 137.07, 137.23,
147.00, 160.29, 176.88; Anal. (C.sub.30H.sub.25FNO.sub.6P)C, H,
N.
[0177] 2-(3-Fluorophenyl)-6-methoxy-4-oxo-1,4-dihydroquinolin-5-yl
dihydrogen phosphate (52). Compound 51 (0.25 g, 0.46 mmol) was
allowed to react in the same manner as described in the preparation
of compound 49 to give 52. Yellow solid; yield: 63.7%; mp
179-181.degree. C.; MS (ESI): m/z 366 (M+H).sup.+; .sup.1H-NMR
(D.sub.2O+NaOD, 200 MHz): .delta. 3.76 (s, 3H), 6.53 (s, 1H), 7.05
(1, =8.4 Hz, 1H), 7.24-7.60 (m, 5H); Anal.
(C.sub.16H.sub.13FNO.sub.6P) C, H, N.
[0178] Sodium
2-(3-fluorophenyl)-6-methoxy-4-oxo-1,4-dihydroquinolin-5-yl
phosphate (53). Compound 52 (0.73 g, 2.0 mmol) was allowed to react
in the same manner as described in the preparation of compound 50
to give 53. Yellow solid; yield: 48.0%; mp>300.degree. C.; MS
(ESI): m/z 410 (M+H).sup.+; .sup.1H-NMR (D.sub.2O, 200 MHz):
.delta. 3.72 (s, 3H), 6.54 (s, 3H), 6.99 (t, J=7.8 Hz, 1H),
7.15-7.55 (m, 5H); Anal. (C.sub.16H.sub.11FNNa.sub.2O.sub.6P)C, H,
N.
I-2. Anticancer Activity
In Vitro Tests of Compounds
[0179] MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide) assays..sup.21,22 HL-60, HCT-116, Hep 3B, H460, Detroit
551 and HT29/FuR cells were treated with tested compounds for the
indicated periods. After treatment, cells were washed once with PBS
and incubated with MTT (Sigma, St. Louis, Mo., USA) for 2 h. The
formazan precipitate was dissolved in 150 .mu.L of DMSO, and the
absorbance was measured with an ELISA reader at 570 nm.
Results
[0180] The cytotoxicity of 5,6-(6,7-) disubstituted
2-(fluorophenyl)quinolin-4-ones (16-21, 37-45) and CHM-2133, were
screened against HL-60, HCT-116, Hep3B, H-460 and Detroit 551
normal human cell, and the results were summarized in Table 1.
Among 5,6-dimethoxy derivatives (16-18), the 3-fluoro derivative
(17) exhibited the strongest cytotoxicity, though relatively weaker
than that of our positive control CHM-2133. Meanwhile, both
compounds 19 and 20, having methylenedioxy entity bridging the
5,6-position of their quinoline ring, demonstrated significant
cytotoxicity, although weaker than CHM-2133. Then, while all of the
three 5-hydroxy-6-methoxy derivatives (37-39) showed significant
cytotoxicity, compounds 37 and 38, with 2'- or 3'-fluorosubstituent
on 2-phenyl group, demonstrated greater cytotoxicity, but lower
toxicity toward Detroit 551 normal human cell than CHM-2133.
Following the same trend, it was found that, among 5,6-dihydroxy
(40-42) and 7-hydroxy-6-methoxy (43-45) derivatives, those with
2'-fluoro (40, 43) and 3'-fluoro group (41, 44) demonstrated
greater cytotoxicity. In general, the cytotoxicity of
4'-fluorophenyl derivatives (18, 21, 39, 42 and 45) was found to be
weaker than 2'-fluorophenyl derivatives (16, 19, 37, 40 and 43) and
3'-fluorophenyl derivatives (17, 20, 38, 41 and 44). Among them,
compounds 37 and 38 are considered the most promising anticancer
agents. None of the tested compounds showed noticeable cytotoxicity
toward the Detroit 551 normal human cells. Below and Table 1 shows
structures and cytotoxicities of CHM-2133 and target compounds
16-45.
##STR00017##
TABLE-US-00001 TABLE 1 IC.sub.50 .sup.a(.mu.M) Comp'd R.sub.2
R.sub.3 R.sub.4 HL-60 HCT116 Hep3B H460 Detroit 551 HT29/5FuR
CHM-21 -- -- -- 0.08 0.15 0.13 0.14 8.2 -- 33 16 F H H 3.7 >20
>20 >20 >20 2.03 17 H F H 1.3 1.2 2.6 3.5 100 1.96 18 H H
F 2.0 >20 >20 >20 >20 2.02 19 F H H 1.0 2.1 1.9 4.5
>10 0.69 20 H F H 0.7 2.5 2.4 3.2 >5 0.82 21 H H F >10
>10 >10 >10 >10 0.53 37 F H H 0.067 0.05 0.05 0.11 10
0.20 38 H F H 0.039 0.073 0.078 0.088 >50 0.26 39 H H F 1.8 2.4
11.0 8.8 >25 0.33 40 F H H 0.5 0.6 3.9 4.1 >100 1.63 41 H F H
0.3 8.2 6.9 6.1 >100 0.53 42 H H F 38.6 >100 100 100 >100
NA.sup.b 43 F H H 1.3 5.8 5.3 4.4 29.7 0.29 44 H F H 0.9 1.1 5.3
4.8 10 0.30 45 H H F 38.2 >100 >100 >100 >100 0.37
Human tumor cells were treated with different concentrations of
samples for 48 h. .sup.aData was presented as IC.sub.50 (.mu.M, the
concentration of 50% proliferation-inhibitory effect). .sup.bNA =
Not assayed.
In Vivo Antitumor Activity Assay.
[0181] The Hep-3B tumor cell line was purchased from American Type
Culture Collection (ATCC.TM. HB-8064, human ovarian carcinoma
cells). The culture medium contained DMEM, 90%; Fetal Bovine Serum,
10% and 1% penicillin-streptomycin. The tumor cells were incubated
in an atmosphere containing 5% CO.sub.2 at 37.degree. C.
[0182] Balb/c Nude mice used in this study were male, 4-6 weeks
age, weighing 18-20 g and provided by National Animal Center. All
animals were housed in Individually Ventilated Cages Racks (IVC
Racks, 36 Mini Isolator system) under Specific Pathogen-Free (SPF)
condition throughout the experiment. Each cage (in cm, 26.7
length.times.20.7 width.times.14.0 height) was sterilized with
autoclave and contained 8 mice, and then the animals were
maintained in a hygienic environment under controlled temperature
(20-24.degree. C.) and humidity (40%-70%) with 12 hour light/dark
cycle. The animals were given free access to sterilized lab chow
and sterilized distilled water ad libilum. All aspects of this
work, i.e., housing, experimentation and disposal of animals were
performed in general accordance with the Guide for the Care and Use
of Laboratory Animals (National Academy Press, Washington, D.C.,
1996).
[0183] In the xenograft tumor model of human ovarian carcinoma cell
lines (Hep-3B, ATCC HB-8064) in male Balb/c Nude mice, the
compounds 50 at doses at 7.5, 15 and 30 mg/kg (i.v. or p.o., bid)
was administered five days per week for four consecutive weeks by
p.o. or i.v. and ceased at Day 28. The compounds 53 at doses at
7.5, 15 and 30 mg/kg (i.v. or p.o., qd) was administered five days
per week for four consecutive weeks and ceased at Day 28. The tumor
size, body weight was monitored and recorded for 28 days. Human
ovarian carcinoma cells (HEP-3B, ATCC HB-8064) with
2.times.10.sup.6 cells in 0.1 ml were injected subcutaneously into
the right flank of the mice. When the tumor growth reached >10.0
mm.sup.3 in volume (assumed as day 0), the tumor-bearing animals
were assigned into several groups (8 animals in each group) for
study.
[0184] The body weight and tumor size were measured and recorded
every 7 days during the experimental periods of 28 days. Tumor
volume (mm.sup.3) was estimated according to the formula of
length.times.(width).times.0.5 in mm.sup.3. Tumor growth inhibition
was calculated as T/C (treatment/control) by the following formula:
T/C=(Tn-T.sub.0)/(Cn-C.sub.0).times.100% (T.sub.0: Tumor volume of
treated group in Day 0; Tn: Tumor volume of treated group in Day n;
C.sub.0: Tumor volume of control group in Day 0; Cn: Tumor volume
of control group in Day n).
Results
[0185] In vivo antitumor activity of compounds 50 and 53. The water
soluble diphosphate of 38 (50) was evaluated in Hep3B xenograft
nude mice model administrated by p.o. and i.v. routes. Results in
FIG. 4 (A-F) indicated that the antitumor activity of compound 50
followed dose- and time-dependent manner, and at 7.5 mg/kg (i.v. or
p.o., bid) its antitumor activity exceeded that of doxorubicin (5
mg/kg, i.v., qd; 10 mg/kg, p.o., qd). During the course of
antitumor evaluation, no significant body weight changes were
detected either in tested or control mice (FIGS. 4C and 4F). At the
same time, the antitumor activity of monophosphate derivative of
compound 38 (53) was evaluated with the same animal model by oral
route at the dose of 7.5, 15, 30 mg/kg/day. As shown by the results
in FIG. 5A, compound 53 induced dose- and time-dependent inhibition
of Hep3B tumor growth. Significant tumor growth suppression, at an
extent exceeding that observed after 10 mg/kg/day oral dosing of
doxorubicin, was detected after 7.5 mg/kg/day oral dosing of
compound 53. Near complete tumor suppression was observed after 30
mg/kg/day oral dosing. Again during the course of antitumor
evaluation, no significant body weight changes were detected in
either the tested or the control mice. Similarly, the dose- and
time-dependent antitumor test result by i.v. administration,
summarized in FIG. 5B, resembled that administrated through p.o.
route, and showed slight better antitumor activity in general.
II. B Series
Chemical Synthesis
[0186] The intermediates, 5-alkylamino-2-aminoacetophenones (60-62)
were prepared according to the methods reported before. As shown in
Scheme 6, the starting 3-chloroacetophenone (54) was first nitrated
with HNO.sub.3/H.sub.2SO.sub.4 to form the
5-chloro-2-nitroacetophenone (55) and 5-chloro-4-nitroacetophenone
(56). Compound 55 was reacted separately with various alkylamines
to yield the corresponding 5-alkylamino-2-nitroacetophenones
(57-59). Catalytic hydrogenation of compounds 57-59 yielded the
corresponding 5-alkylamino-2-aminoacetophenones (60-62). L. Li, K.
K. Wang, S. C. Kuo, T. S. Wu, D. Lednicer, C. M. Lin, E. Hamel and
K. H. Lee, J. Med. Chem., 37, 1126-35. (1994), which is herein
incorporated by reference in its entirety.
[0187] The synthesis of other intermediated, substituted benzoyl
chlorides (83-91) is illustrated in Scheme 7 and Scheme 8.
Esterification of substituted benzoic acids (63-67) yielded the
corresponding ester (68-72). Compounds 68-71 were treated with
benzyl bromide to yield the corresponding benzyloxy derivatives
(73-76). On the other hand, compound 72 was treated with
diiodomethane to afford ethyl 5,6-methylenedioxobenzoate (77). When
compounds 73-77 were hydrolyzed with NaOH to yield the
corresponding acids (78-82) which were allowed to react with
SOCl.sub.2 to afford the corresponding acid chlorides (83-87).
[0188] Finally, as shown in Scheme
8,5-alkylamino-2-aminoacetophenones (60-62) were reacted separately
with substituted benzoyl chlorides (83-91) to yield the
corresponding amides (92-112), which were subsequently cyclized in
dioxane in the presence of NaOH, to afford the target compounds
((113-133).
[0189] The compound 138 was derived into a phosphate (147)
following the synthetic method in Scheme 10. As illustrated,
compound 138 was first reacted with tetrabenzylpyrophosphate 46 in
THF, in the presence of NaH, to give bis(dibenzylphosphate) (145)
which, without further purification, was subsequently dissolved in
MeOH and stirred at 25.degree. C. to yield a monophosphate (146).
The structure of compound 146 was confirmed by the chemical shift
of its proton on the 3-position (.delta. 6.39) in the .sup.1H-NMR
spectrum. Subsequently, compound 146 was debenzylated catalytically
to afford a stable monophosphoric acid (147).
##STR00018##
##STR00019## ##STR00020##
##STR00021##
##STR00022##
##STR00023##
Examples
[0190] General Experimental Procedures. All of the solvents and
reagents were obtained commercially and used without further
purification. The progress of all reactions was monitored by TLC on
2.times.6 cm pre-coated silica gel 60 F.sub.254 plates of thickness
0.25 mm (Merck). The chromatograms were visualized under UV 254-366
nm. The following adsorbent was used for column chromatography:
silica gel 60 (Merck, particle size 0.040-0.063 mm). Melting points
were determined with a Yanaco MP-500D melting point apparatus and
are uncorrected. IR spectra were recorded on Shimadzu
IR-Prestige-21 spectrophotometers as KBr pellets. NMR spectra were
obtained on a Bruker Avance DPX-200 FT-NMR spectrometer in
CDCl.sub.3 or DMSO. The following abbreviations are used: s,
singlet; d, doublet; t, triplet; q, quartet; dd, double doublet;
and m, multiplet. MS spectra were measured with an HP 5995 GC-MS
instrument. Elemental analyses (C, H, and N) were carried out at
the instruments center of National Chung Hsing University,
Taichung, Taiwan and performed on a Perkin-Elmer 2400 Series II
CHNS/O analyzer or Elementar vario EL III Heraeus CHNOS Rapid F002
and the results were within .+-.0.4% of the calculated values.
[0191] 5-Chloro-2-nitroacetophenone (55). 65% HNO.sub.3 (80 ml) was
stirred at -5.degree. C..+-.1.degree. C. and 98% H.sub.2SO.sub.4
(10 mix 10) was added dropwise. To the stirring solution of
HNO.sub.3/H.sub.2SO.sub.4 was added 3-chloroacetophenone (54) (12.0
g, 77.6 mmol). The mixture was stirred at -5.degree..+-.1.degree.
for 3 h and poured into crushed ice, and extracted with
CH.sub.2Cl.sub.2. The extract was dried over MgSO.sub.4 and
evaporated. The crude product was purified by column chromatography
(silica gel, n-hexane/EtOAc=15:1) to give 55 as yellow solid (9.3
g, 46.6 mmol). Yield: 55.8%; mp 47-49.degree. C.; .sup.1H-NMR
(CDCl.sub.3, 200 MHz): .delta. 2.48 (s, 3H), 7.32 (d, J=2.4 Hz,
1H), 7.49 (dd, J=8.8, 2.2 Hz, 1H), 8.00 (d, J=8.8 Hz, 1H);
.sup.13C-NMR (CDCl.sub.3, 50 MHz) .delta.: 198.27, 143.78, 141.05,
139.44, 130.55, 127.36, 125.91, 30.06; Anal. Calcd for
C.sub.8H.sub.6ClNO.sub.3: C, 48.14; H, 3.03; N, 7.02.
[0192] 5-Morpholino-2-nitroacetophenone (57). To a solution of 55
(3.0 g, 15.0 mmol) in DMF (25 ml) were added K.sub.2CO.sub.3 (8.3
g, 60.1 mmol) and morpholine (3.2 g, 37.5 mmol). The mixture was
refluxed for 3 h and then poured into crushed ice. The precipitate
was collected and washed with H.sub.2O. The crude product was
purified by column chromatography (silica gel, CH.sub.2Cl.sub.2:
n-hexane=2:1) to give 57 as yellow solid (3.4 g, 13.6 mmol). Yield:
90.4%; mp 124-126.degree. C.; .sup.1H-NMR (CDCl.sub.3, 200 MHz):
.delta. 2.45 (s, 3H), 3.33-3.38 (m, 4H), 3.78-3.82 (m, 4H), 6.53
(d, J=2.8 Hz, 1H), 6.78 (dd, J=9.4, 2.8 Hz, 1H), 8.02 (d, J=9.4 Hz,
1H); .sup.13C-NMR (CDCl.sub.3, 50 MHz) .delta.: 201.30, 154.60,
141.53, 134.90, 127.04, 112.88, 109.83, 66.20, 46.84, 30.52; Anal.
Calcd for C.sub.12H.sub.14N.sub.2O.sub.4: C, 57.59; H, 5.64; N,
11.19.
[0193] 5-Pyrrolidino-2-nitroacetophenone (58) was obtained from 30
and pyrrolidine, using the same synthetic procedure as for 57 to
give 58 as yellow solid (3.2 g, 13.7 mmol); yield 90.9%; mp
119-121.degree. C.; .sup.1H-NMR (CDCl.sub.3, 200 MHz): .delta. 2.04
(m, 4H), 2.45 (s, 3H), 3.37 (m, 4H), 6.19 (d, J=2.6 Hz, 1H), 6.44
(dd, J=9.4, 2.6 Hz, 1H), 8.02 (d, J=9.4 Hz, 1H); .sup.13C-NMR
(CDCl.sub.3, 200 MHz) .delta.: 201.80, 151.61, 142.16, 132.54,
127.37, 111.08, 107.87, 48.07, 30.58, 25.37; Anal. Calcd for
C.sub.12H.sub.14N.sub.2O.sub.3: C, 61.53; H, 6.02; N, 11.96.
[0194] 5-Dimethylamino-2-nitroacetophenone (59) was obtained from
30 and dimethylamine hydrochloride, using the same synthetic
procedure as for 57 to give 59 as yellow solid (2.3 g, 11.0 mmol);
yield 88.2%; mp 125-127.degree. C.; .sup.1H-NMR (CDCl.sub.3, 200
MHz): .delta. 2.45 (s, 3H), 3.08 (s, 6H), 6.31 (d, J=2.8 Hz, 1H),
6.58 (dd, J=9.4, 2.8 Hz, 1H), 8.02 (d, J=9.4 Hz, 1H); .sup.13C-NMR
(CDCl.sub.3, 50 MHz) .delta.: 201.76, 153.98, 141.88, 133.02,
127.19, 110.83, 107.66, 40.30, 30.56
[0195] 5-Morpholino-2-aminoacetophenone (60). A solution of 57 (1.5
g, 5.9 mmol)in CH.sub.2Cl.sub.2 (30 ml) was hydrogenated in the
presence of 10% Pd/C (0.4 g) at 25.degree. C. for 8 h. The catalyst
was filtered off and the filtrate was evaporated to give 60 as
yellow solid. (1.25 g, 5.68 mmol); yield 94.6%; .sup.1H-NMR
(CDCl.sub.3, 200 MHz): .delta..delta. 2.45 (s, 3H), 2.9 (m, 4H),
3.68 (m, 4H), 6.67 (d, J-8.8 Hz, 1H), 6.78 (br, 2H), 7.02-7.11 (m,
2H); .sup.13C-NMR (CDCl.sub.3, 50 MHz) .delta.: 200.44, 145.61,
141.51, 126.37, 119.26, 118.40, 118.22, 66.96, 51.57, 27.93; Anal.
Calcd for C.sub.12H.sub.16N.sub.2O.sub.2: C, 65.43; H, 7.32; N,
12.72.
[0196] 5-Pyrrolidino-2-aminoacetophenone (61) was obtained from 58,
using the same synthetic procedure as for 60 to give 61 as orange
solid (1.2 g, 5.9 mmol); yield 91.8%; .sup.1H-NMR
(CDCl.sub.3-d.sub.6, 200 MHz): .delta. 1.86 (m, 4H), 2.45 (s, 3H),
3.10 (m, 4H), 6.42 (br, 2H), 6.62-6.77 (m, 3H); .sup.13C-NMR
(CDCl.sub.3, 50 MHz) .delta.: 200.56, 143.11, 139.23, 121.91,
118.59, 117.86, 113.03, 48.57, 28.47, 25.9; Anal. Calcd for
C.sub.12H.sub.16N.sub.2O: C, 70.56; H, 7.90; N, 13.71.
[0197] 5-Dimethylamino-2-aminoacetophenone (62) was obtained from
59, using the same synthetic procedure as for 60 to give 62 as
orange solid (1.8 g, 10.1 mmol); yield 91.5%; .sup.1H-NMR
(DMSO-d.sub.6, 200 MHz): .delta. 2.45 (s, 3H), 2.71 (s, 6H),
6.64-6.69 (m, 2H), 6.96-7.00 (m, 3H); .sup.13C-NMR (DMSO-d.sub.6,
50 MHz) .delta.: 200.49, 144.66, 141.42, 124.49, 118.46, 117.37,
115.79, 42.34, 28.42
[0198] Ethyl 2-hydroxybenzoate (68). To a solution of
2-hydroxybenzoic acid (63) (5.0 g, 36.2 mmol) in anhydrous EtOH
(150 ml) was added 98% H.sub.2SO.sub.4 (4 ml). The mixture was
refluxed for 4 h and concentrated. The residue was extracted with
CH.sub.2Cl.sub.2 dried over MgSO.sub.4 and evaporated. The crude
was purified by distillation to give 68 as colorless liquid. (5.85
g, 35.21 mmol). Yield: 97.25%; MS (EI, 70 eV): m/z 166.2 (M.sup.+);
.sup.1H-NMR (CDCl.sub.3, 200 MHz): .delta. 1.39 (t, J=7.2 Hz, 3H),
4.37 (q, J=7.2, 7.0 Hz, 2H), 6.81 (t, J=6.6 Hz, 1H), 6.89 (d, J=8.0
Hz, 1H), 7.42 (t, J=7.2 Hz, 1H), 7.82 (dd, J.sub.1=8.0, 1.8 Hz,
1H), 10.83 (s, 1H); .sup.13C-NMR (CDCl.sub.3, 50 MHz) .delta.:
170.20, 161.64, 135.56, 129.89, 119.06, 117.53, 61.40, 14.18; Anal.
Calcd for C.sub.9H.sub.10O.sub.3: C, 65.05; H, 6.07.
[0199] Ethyl 3-hydroxybenzoate (69) was obtained from 64, using the
same synthetic procedure as for 38 to give 39 as white solid. (3.4
g, 20.5 mmol); yield 94.2%; mp 60-62.degree. C.; MS (EI, 70 eV):
m/z 166.2 (M.sup.+); .sup.1H-NMR (CDCl.sub.3, 200 MHz): .delta.
1.36 (t, J=7.2 Hz, 3H), 4.35 (q, J=7.2, 7.0 Hz, 2H), 5.55 (s, 1H),
7.07 (dd, J=2.6, 1.2 Hz, 1H), 7.27 (d, J=7.8 Hz, 1H), 7.55-7.62 (m,
2H); .sup.13C-NMR (CDCl.sub.3, 50 MHz) .delta.: 167.15, 156.07,
131.50, 129.69, 121.36, 120.36, 116.36, 61.43, 14.23; Anal. Calcd
for C.sub.9H.sub.10O.sub.3: C, 65.05; H, 6.07.
[0200] Ethyl 4-hydroxybenzoate (70) was obtained from 65, using the
same synthetic procedure as for 68 to give 70 as white solid. (5.3
g, 31.9 mmol); yield 88.2%; mp 105-107.degree. C.; MS (EI, 70 eV):
m/z 166.2 (M.sup.+); .sup.1H-NMR (CDCl.sub.3, 200 MHz): .delta.
1.36 (t, J=7.2 Hz, 3H), 4.33 (q, J=7.2, 7.0 Hz, 2H), 6.84 (d, J=1.8
Hz, 1H), 6.88 (d, J=1.8 Hz, 1H), 7.90 (d, J=1.8 Hz, 1H), 7.95 (d,
J=1.8 Hz, 1H); .sup.13C-NMR (CDCl.sub.3, 50 MHz) .delta.: 167.13,
160.38, 131.91, 122.44, 115.26, 61.01, 14.30; Anal. Calcd for
C.sub.9H.sub.10O.sub.3: C, 65.05; H, 6.07.
[0201] Ethyl 3-methoxy-4-hydroxybenzoate (71) was obtained from 66,
using the same synthetic procedure as for 68 to give 71 as brown
liquid. (6.3 g, 32.1 mmol); yield 90.9%; MS (EI, 70 eV): m/z 196.2
(M.sup.+); .sup.1H-NMR (CDCl.sub.3, 200 MHz): .delta. 1.35 (t,
J=7.2 Hz, 3H), 3.93 (s, 3H), 4.32 (q, J=7.2, 7.0 Hz, 2H), 6.90 (d,
J=8.2 Hz, 1H), 7.53 (d, J=1.8 Hz, 1H), 7.62 (dd, J=8.2, 1.8 Hz,
1H); .sup.13C-NMR (CDCl.sub.3, 50 MHz) .delta.: 166.44, 149.91,
146.13, 124.10, 122.62, 113.99, 111.70, 60.79, 56.09, 14.37; Anal.
Calcd for C.sub.10H.sub.12O.sub.4: C, 61.22; H, 6.16.
[0202] Ethyl 2,3-dihydroxybenzoate (72) was obtained from 67, using
the same synthetic procedure as for 68 to give 72 as white solid.
(5.4 g, 29.6 mmol); yield 91.4%; mp 92-94.degree. C.; MS (EI, 70
eV): m/z 182.2 (M.sup.+); .sup.1H-NMR (CDCl.sub.3, 200 MHz):
.delta. 1.40 (t, J=7.2 Hz, 3H), 4.38 (q, J=7.2, 7.0 Hz, 2H), 5.18
(br, 1H), 6.70-7.40 (m, 3H), 10.97 (br, 1H); .sup.13C-NMR
(CDCl.sub.3, 50 MHz) .delta.: 170.38, 148.90, 145.00, 120.55,
119.71, 119.45, 119.10, 112.63, 61.61, 14.13; Anal. Calcd for
C.sub.10H.sub.12O.sub.4: C, 59.34; H, 5.53.
[0203] Ethyl 2-(benzyloxy)benzoate (73). To a solution of 68 (5.8
g, 34.9 mmol) in CH.sub.3CN (150 ml) was added K.sub.2CO.sub.3
(10.6 g, 76.8 mmol). The mixture was added benzyl bromide (6.57 g,
38.39 mmol) and refluxed for 8 h under N.sub.2 atmosphere. The
reaction mixture was cooled to 25.degree. and poured into H.sub.2O
(500 ml), and then extracted with CH.sub.2Cl.sub.2. The organic
layer was washed with H.sub.2O, dried over MgSO.sub.4 and
evaporated. The crude products were purified by distillation to
give 73 as colorless liquid. (8.5 g, 33.2 mmol). Yield: 94.71%; MS
(EI, 70 eV): m/z 256.3 (M.sup.+); .sup.1H-NMR (CDCl.sub.3, 200
MHz): .delta. 1.33=(t, J=7.2 Hz, 3H), 4.35 (q, =7.2, 7.0 Hz, 2H),
5.15 (s, 2H), 7.00 (d, =8.0 Hz, 2H), 7.32-7.45 (m, 5H), 7.49 (d,
J=8.2 Hz, 1H), 7.82 (dd, J=8.2, 1.8 Hz, 1H); .sup.13C-NMR
(CDCl.sub.3, 50 MHz) .delta.: 166.60, 158.01, 136.77, 133.25,
131.69, 128.49, 127.80, 126.99, 121.20, 120.56, 113.75, 70.57,
60.93, 14.29; Anal. Calcd for C.sub.16H.sub.16O.sub.3: C, 74.98; H,
6.29.
[0204] Ethyl 3-(benzyloxy)benzoate (74) was obtained from 69, using
the same synthetic procedure as for 73 to give 74 as colorless
liquid. (4.05 g, 15.80 mmol); yield 77.3%; MS (EI, 70 eV): m/z
256.3 (M.sup.+); .sup.1H-NMR (CDCl.sub.3, 200 MHz): .delta. 1.39
(t, J=7.2 Hz, 3H), 4.37 (q, 7.2, 7.0 Hz, 2H), 5.08 (s, 2H),
7.17-7.72 (m, 9H); .sup.13C-NMR (CDCl.sub.3, 200 MHz) .delta.:
166.42, 158.76, 136.66, 131.90, 129.48, 128.67, 128.14, 127.62,
122.24, 119.96, 115.26, 70.14, 61.09, 14.38; Anal. Calcd for
C.sub.16H.sub.16O.sub.3: C, 74.98; H, 6.29.
[0205] Ethyl 4-(benzyloxy)benzoate (75) was obtained from 70, using
the same synthetic procedure as for 73 to give 75 as colorless
liquid. (7.6 g, 29.6 mmol); yield 92.5%; MS (EI, 70 eV): m/z 256.3
(M.sup.+); .sup.1H-NMR (CDCl.sub.3, 200 MHz): .delta. 1.35 (t,
J=7.2 Hz, 3H), 4.32 (q, J=7.2, 7.0 Hz, 2H), 5.09 (s, 2H), 6.95 (d,
J=2.0 Hz, 1H), 6.98 (d, J=2.0 Hz, 1H), 7.31-7.41 (m, 5H), 7.95 (d,
J=2.0 Hz, 1H), 7.99 (d, J=2.0 Hz, 1H); .sup.13C-NMR (CDCl.sub.3, 50
MHz) .delta.: 166.36, 162.39, 136.28, 131.55, 129.02, 128.67,
128.19, 127.48, 123.18, 114.41, 70.08, 60.65, 14.37; Anal. Calcd
for C.sub.16H.sub.16O.sub.3: C, 74.98; H, 6.29.
[0206] Ethyl 4-(benzyloxy)-3-methoxybenzoate (76) was obtained from
71, using the same synthetic procedure as for 73 to give 76 as
brown solid. (8.5 g, 29.7 mmol); yield 91.5%; mp 73-75.degree. C.;
MS (EI, 70 eV): 286.4 (NC); .sup.1H-NMR (CDCl.sub.3, 200 MHz):
.delta..delta. 1.35 (t, J=7.2 Hz, 3H), 3.91 (s, 3H), 4.32 (q, 17.2,
7.0 Hz, 2H), 5.18 (s, 2H), 6.85 (d, J=8.4 Hz, 1H), 7.27-7.62 (m,
7H); .sup.13C-NMR (CDCl.sub.3, 50 MHz) .delta.: 166.38, 152.01,
149.12, 136.40, 128.64, 128.05, 127.22, 123.29, 112.46, 70.77,
60.79, 56.07, 14.39; Anal. Calcd for C.sub.17H.sub.18O.sub.4: C,
71.31; H, 6.34.
[0207] Ethyl 2,3-methylenedioxybenzoate (77) was obtained from 72
and diiodomethane, using the same synthetic procedure as for 73 to
give 77 as colorless liquid. (2.8 g, 14.4 mmol); yield 87.6%; mp
90-92.degree. C.; MS (EI, 70 eV): ml: 194.1 (M.sup.+); .sup.1H-NMR
(CDCl.sub.3, 200 MHz): .delta. 1.35 (t, J=7.2 Hz, 3H), 4.34 (q,
J=7.2, 7.0 Hz, 2H), 6.04 (s, 2H), 6.80 (t, J=7.8 Hz, 3H), 6.92 (dd,
7.8, 1.4 Hz, 1H), 7.37 (dd, J=7.8, 1.4 Hz, 1H); .sup.13C-NMR
(CDCl.sub.3, 50 MHz) .delta.: 164.42, 148.68, 148.41, 122.66,
121.10, 113.28, 112.12, 101.83, 60.98, 14.30; Anal. Calcd for
C.sub.10H.sub.10O.sub.4: C, 61.85; H, 5.19.
[0208] 2-(Benzyloxy)benzoic acid (78). To a suspension of 73 (4.0
g, 15.6 mmol) in H.sub.2O (150 ml) were added NaOH (3.1 g, 78.0
mmol) and EtOH (5 ml). The mixture was reflux for 12 h, and cooled
to 25.degree. C. The solid was filtered out and the filtrate was
acidified with 2N HCl. The precipitate was collected and washed
with H.sub.2O. The crude product was recrystallized from to give 78
as white solid. (3.0 g, 13.2 mmol). Yield: 84.6%; mp 73-75.degree.
C.; MS (EI, 70 eV): m/z 228.3 (M.sup.+); .sup.1H-NMR (CDCl.sub.3,
200 MHz): .delta. 5.27 (s, 2H), 7.08-7.54 (m, 8H), 6.93 (dd, J=8.0,
1.8 Hz, 1H); .sup.13C-NMR (CDCl.sub.3, 50 MHz) .delta.: 165.43,
157.40, 135.02, 134.34, 133.88, 129.16, 127.92, 122.44, 118.09,
113.11, 72.23; Anal. Calcd for C.sub.14H.sub.12O.sub.3: C, 73.67;
H, 5.30.
[0209] 3-(Benzyloxy)benzoic acid (79) was obtained from 74, using
the same synthetic procedure as for 48 to give 49 as white solid.
(3.1 g, 13.6 mmol). Yield: 87.4%; mp 120-122.degree. C.; MS (EI, 70
eV): m/z 228.3 (M.sup.+); .sup.1H-NMR (DMSO-d.sub.6, 200 MHz):
.delta. 3.37 (br, 1H), 5.12 (s, 2H), 7.19-7.50 (m, 9H);
.sup.13C-NMR (DMSO-d.sub.6, 50 MHz) .delta.: 167.55, 18.77, 137.26,
132.69, 130.19, 128.90, 128.33, 128.10, 122.25, 120.15, 115.36;
Anal. Calcd for C.sub.14H.sub.2O.sub.3: C, 73.67; H, 5.30.
[0210] 4-(Benzyloxy)benzoic acid (80) was obtained from 75, using
the same synthetic procedure as for 78 to give 80 as white solid.
(6.2 g, 27.2 mmol). Yield: 92.0%; mp 195-197.degree. C.; MS (EI, 70
eV): m/z 228.3 (M.sup.+); .sup.1H-NMR (DMSO-d.sub.6, 200 MHz):
.delta. 5.10 (s, 2H), 6.96 (d, J=2.0 Hz, 1H), 7.00 (d, J=2.0 Hz,
1H), 7.28-7.44 (m, 5H), 7.82 (d, J=2.0 Hz, 1H), 7.86 (d, J=2.0 Hz,
1H); .sup.13C-NMR (DMSO-d.sub.6, 50 MHz) .delta.: 168.50, 161.37,
137.20, 131.53, 128.91, 128.37, 128.21, 127.00, 114.55, 69.78;
Anal. Calcd for C.sub.14H.sub.12O.sub.3: C, 73.67; H, 5.30.
[0211] 4-(Benzyloxy)-3-methoxybenzoic acid (81) was obtained from
76, using the same synthetic procedure as for 78 to give 81 as
white solid. (7.6 g, 29.4 mmol). Yield: 99.5%; mp 159-162.degree.
C.; MS (EI, 70 eV): m/z 258.3 (M.sup.+); .sup.1H-NMR (DMSO-d.sub.6,
200 MHz): .delta. 3.76 (s, 3H), 5.11 (s, 2H), 7.10 (d, J=8.4 Hz,
1H), 7.29-7.43 (m, 6H), 7.50 (dd, J=8.4, 1.8 Hz, 1H); .sup.13C-NMR
(DMSO-d.sub.6, 50 MHz) .delta.: 167.53, 152.03, 149.01, 136.99,
128.92, 128.38, 123.68, 123.47, 112.86, 112.58, 70.30, 55.94; Anal.
Calcd for C.sub.15H.sub.14O.sub.4: C, 69.76; H, 5.46.
[0212] 2,3-Methylenedioxybenzoic acid (82) was obtained from 77,
using the same synthetic procedure as for 78 to give 82 as white
solid. (2.3 g, 13.8 mmol). Yield: 96.0%; mp 188-190.degree. C.; MS
(EI, 70 eV): m/z 166.2 (M.sup.+); .sup.1H-NMR (DMSO-d.sub.6, 200
MHz): .delta. 6.07 (s, 2H), 7.05 (d, J=8.2 Hz, 1H), 7.25 (t, J=7.6
Hz, 1H), 7.06 (dd, J=7.6, 1.2 Hz, 1H), 7.23 (dd, J=7.6, 1.2 Hz,
1H), 12.95 (br, 1H); .sup.13C-NMR (DMSO-d.sub.6, 50 MHz) .delta.:
165.56, 148.91, 148.51, 122.94, 121.58, 113.80, 112.46, 102.11;
Anal. Calcd for C.sub.8H.sub.6O.sub.4: C, 57.84; H, 3.64.
[0213] 2-Benzyloxybenzoyl chloride (83). To a suspension of 78 (3.1
g, 13.6 mmol) in dry toluene (150 ml)was added SOCl.sub.2 (12.9 g,
109.1 mmol). The mixture was reflux for 8 h and evaporated to give
83 as yellow liquid to use directly in the next step. (2.55 g, 10.3
mmol). Yield: 79.07%.
[0214] 3-Benzyloxybenzoyl chloride (84) was obtained from 79, using
the same synthetic procedure as for 53 to give 54 as yellow liquid
to use directly in the next step. (2.5 g, 10.1 mmol). Yield:
74.2%.
[0215] 4-Benzyloxybenzoyl chloride (85) was obtained from 80, using
the same synthetic procedure as for 53 to give 55 as yellow liquid
to use directly in the next step. (2.4 g, 9.7 mmol). Yield:
79.5%.
[0216] 4-Benzyloxy-3-methoxybenzoyl chloride (86) was obtained from
81, using the same synthetic procedure as for 83 to give 86 as
brown liquid to use directly in the next step. (4.5 g, 16.3 mmol).
Yield: 84.6%.
[0217] 2,3-Methylenedioxybenzoyl chloride (87) was obtained from
82, using the same synthetic procedure as for 83 to give 87 as
white solid to use directly in the next step. (1.7 g, 9.2 mmol).
Yield: 76.5%.
[0218] 2,3-Dimethoxybenzoyl chloride (88) was obtained from 83,
using the same synthetic procedure as for 53 to give 58 as yellow
liquid to use directly in the next step. (2.8 g, 14.0 mmol). Yield:
84.8%.
[0219] 2,5-Dimethoxybenzoyl chloride (89) was obtained from 84,
using the same synthetic procedure as for 55 to give 59 as yellow
liquid to use directly in the next step. (2.3 g, 11.5 mmol). Yield:
83.5%.
[0220] N-(2-Acetyl-4-morpholinophenyl)-2-benzyloxybenzamide (92).
To a solution of 60 (1.3 g, 5.9 mmol) in THF (150 ml) was added
Et.sub.3N (8 ml). The mixture was stirred at 0.degree. C. and 83
(1.7 g, 7.1 mmol) was added dropwise. The reaction mixture was
stirred at 25.degree. C. for 2 h and poured into crushed ice and
extracted with CH.sub.2Cl.sub.2. The extract was washed with
H.sub.2O, dried over MgSO.sub.4 and evaporated. The crude product
was purified by column chromatography (silica gel,
CH.sub.2Cl.sub.2) to give 92 as yellow solid. (2.1 g, 4.9 mmol).
Yield: 83.3%; mp 144-146.degree. C.; MS (EI, 70 eV): m/z 430.2
(M.sup.+); .sup.1H-NMR (CDCl.sub.3, 200 MHz): .delta. 2.51 (s, 3H),
3.14 (m, 4H), 3.87 (m, 4H), 5.46 (s, 2H), 6.95-7.05 (m, 2H), 7.15
(dd, J=9.2, 3.0 Hz, 1H), 7.22-7.44 (m, 7H), 8.10 (dd, J=7.6, 1.8
Hz, 1H), 8.37 (d, J=9.2 Hz, 1H), 12.25 (s, 1H); .sup.13C-NMR
(CDCl.sub.3, 50 MHz) .delta.: 201.16, 164.61, 156.37, 136.77,
132.69, 132.11, 128.54, 127.79, 126.98, 125.30, 123.69, 122.22,
121.16, 117.82, 113.28, 70.46, 66.78, 49.94, 28.58; Anal. Calcd for
C.sub.26H.sub.26N.sub.2O.sub.4; C, 72.54; H, 6.09; N, 6.51.
[0221] N-(2-Acetyl-4-pyrrolidinophenyl)-2-benzyloxybenzamide (93)
was obtained from 61 and 83, using the same synthetic procedure as
for 92. The crude product was purified by column chromatography
(silica gel, CHCl.sub.3/n-hexane=10:1) to give 93 as yellow solid.
(1.6 g, 3.9 mmol); yield 76.4%; mp 160-161.degree. C.; MS (EI, 70
eV): m/z 414.2 (M.sup.+); .sup.1H-NMR (CDCl.sub.3, 200 MHz):
.delta. 2.02 (m, 4H), 2.51 (s, 3H), 3.30 (m, 4H), 5.45 (s, 2H),
6.85-7.45 (m, 10H), 8.1 (dd, J=7.8, 1.6 Hz, 1H), 8.67 (d, J=9.2 Hz,
1H), 12.07 (s, 1H); .sup.13C-NMR (CDCl.sub.3, 50 MHz) .delta.:
201.71, 164.15, 156.31, 143.73, 136.68, 132.02, 128.52, 127.74,
12.700, 125.89, 124.04, 121.10, 117.30, 113.25, 112.63, 70.45,
47.89, 28.62, 25.44; Anal. Calcd for
C.sub.26H.sub.26N.sub.2O.sub.3; C, 75.34; H, 6.32; N, 6.76.
[0222] N-(2-Acetyl-4-dimethylaminophenyl)-2-benzyloxybenzamide (94)
was obtained from 62 and 53, using the same synthetic procedure as
for 92. The crude product was purified by column chromatography
(silica gel, CHCl.sub.2) to give 94 as yellow solid. (2.2 g, 5.7
mmol); yield 77.7%; mp 132-134.degree. C.; MS (EI, 70 eV): m/z
388.2 (M.sup.+); .sup.1H-NMR (CDCl.sub.3, 200 MHz): .delta. 2.51
(s, 3H), 2.95 (s, 6H), 5.46 (s, 2H), 7.00 (dd, J=9.2, 2.6 Hz, 1H),
7.05-7.45 (m, 9H), 8.10 (dd, J=7.8, 1.8 Hz, 1H), 8.71 (d, J=9.2 Hz,
1H), 12.13 (s, 1H); .sup.13C-NMR (CDCl.sub.3, 50 MHz) .delta.:
201.55, 164.34, 156.34, 146.04, 136.83, 132.49, 132.05, 130.31,
128.53, 127.77, 127.01, 125.03, 123.95, 123.85, 121.12, 118.81,
114.34, 113.28, 70.47, 41.03, 28.59; Anal. Calcd for
C.sub.24H.sub.24N.sub.2O.sub.3; C, 74.21; H, 6.23; N, 7.21.
[0223] N-(2-Acetyl-4-morpholinophenyl)-3-benzyloxybenzamide (95)
was obtained from 60 and 84, using the same synthetic procedure as
for 92. The crude product was purified by column chromatography
(silica gel, CHCl.sub.3/n-hexane=8:1) to give 95 as yellow solid.
(1.15 g, 2.67 mmol); yield 84.1%; mp 140-142.degree. C.; MS (EI, 70
eV): m/z 430.2 (M.sup.+); .sup.1H-NMR (CDCl.sub.3, 200 MHz):
.delta. 2.67 (s, 3H), 3.13 (m, 4H), 3.9 (m, 4H), 5.13 (s, 2H), 6.95
(m, 1H), 7.05 (m, 1H), 7.22 (m, 1H), 7.23-7.41 (m, 7H), 8.10 (m,
1H), 8.37 (d, J=9.2 Hz, 1H), 12.35 (s, 1H); .sup.13C-NMR
(CDCl.sub.3, 50 MHz) .delta.: 203.05, 165.46, 159.14, 136.66,
136.48, 134.56, 129.82, 128.60, 128.06, 127.61, 123.38, 122.94,
122.04, 119.47, 119.09, 118.41, 113.44, 70.14, 66.75, 49.87, 28.58;
Anal. Calcd for C.sub.26H.sub.26N.sub.2O.sub.4; C, 72.54; H, 6.09;
N, 6.51.
[0224] N-(2-Acetyl-4-pyrrolidinophenyl)-3-benzyloxybenzamide (96)
was obtained from 61 and 84, using the same synthetic procedure as
for 92. The crude product was purified by column chromatography
(silica gel, CH.sub.2Cl.sub.2/n-hexane=5:1) to give 96 as yellow
solid. (1.05 g, 2.53 mmol); yield 74.1%; mp 131-133.degree. C.; MS
(EI, 70 eV): m/z 414.2 (M.sup.+); .sup.1H-NMR (CDCl.sub.3, 200
MHz): .delta. 2.02 (m, 4H), 2.67 (s, 3H), 3.30 (m, 4H), 5.14 (s,
2H), 6.83-7.67 (m, 11H), 8.78 (d, J=9.2 Hz, 1H), 12.20 (s, 1H);
.sup.13C-NMR (CDCl.sub.3, 50 MHz) .delta.: 203.51, 165.07, 159.12,
143.54, 136.88, 136.75, 129.71, 128.59, 128.02, 127.62, 123.32,
122.33, 119.41, 118.85, 118.54, 113.34, 110.89, 70.13, 47.99,
28.57, 25.42; Anal. Calcd for C.sub.26H.sub.26N.sub.2O.sub.3; C,
75.34; H, 6.32; N, 6.76.
[0225] N-(2-acetyl-4-dimethylaminophenyl)-3-(benzyloxy)benzamide
(97) was obtained from 62 and 84, using the same synthetic
procedure as for 92. The crude product was purified by column
chromatography (silica gel, CH.sub.2Cl.sub.2) to give 97 as yellow
solid. (1.6 g, 4.1 mmol); yield 73.4%; mp 147-149.degree. C.; MS
(EI, 70 eV): m/z 388.2 (M.sup.+); .sup.1H-NMR (CDCl.sub.3, 200
MHz): .delta. 2.66 (s, 3H), 2.94 (s, 6H), 5.14 (s, 2H), 6.83 (d,
6.4 Hz, 1H), 7.13-7.69 (m, 10H), 7.57-7.67 (m, 2H), 8.80 (d, J=9.2
Hz, 1H), 12.26 (s, 1H); .sup.13C-NMR (CDCl.sub.3, 50 MHz) .delta.:
203.43, 165.18, 159.12, 146.03, 136.74, 131.68, 129.75, 128.60,
128.04, 127.63, 123.11, 122.11, 119.78, 119.43, 118.90, 114.71,
113.38, 70.12, 40.88, 28.57; Anal. Calcd for
C.sub.24H.sub.24N.sub.2O.sub.3; C, 74.21; H, 6.23; N, 7.21.
[0226] N-(2-Acetyl-4-morpholinophenyl)-4-benzyloxybenzamide (98)
was obtained from 60 and 85, using the same synthetic procedure as
for 92. The crude product was purified by column chromatography
(silica gel, EtOAc/CH.sub.2Cl.sub.2=1:2) to give 98 as yellow
solid. (1.5 g, 3.5 mmol); yield 64.0%; mp 172-175.degree. C.; MS
(EI, 70 eV): m/z 430.2 (M.sup.+); .sup.1H-NMR (CDCl.sub.3, 200
MHz): .delta. 2.67 (s, 3H), 3.14 (m, 4H), 3.88 (m, 4H), 5.05 (s,
2H), 6.99-7.43 (m, 9H), 7.97 (d, J=2.0 Hz, 1H), 8.00 (d, J=2.0 Hz,
1H), 8.86 (d, J=9.2 Hz, 1H), 12.30 (s, 1H); .sup.13C-NMR
(CDCl.sub.3, 50 MHz) .delta.: 203.13, 165.27, 163.55, 161.66,
146.00, 136.37, 135.19, 132.83, 129.28, 128.67, 128.17, 127.48,
123.68, 122.71, 122.01, 118.62, 114.86, 70.13, 66.70, 50.09, 28.63;
Anal. Calcd for C.sub.26H.sub.26N.sub.2O.sub.4; C, 72.54; H, 6.09;
N, 6.51.
[0227] N-(2-Acetyl-4-pyrrolidinophenyl)-4-benzyloxybenzamide (99)
was obtained from 61 and 85, using the same synthetic procedure as
for 92. The crude product was purified by column chromatography
(silica gel, EtOAc/CH.sub.2Cl.sub.2=1:4) to give 99 as yellow
solid. (1.6 g, 3.9 mmol); yield 71.7%; mp 175-178.degree. C.; MS
(EI, 70 eV): m/z 414.2 (M.sup.+); .sup.1H-NMR (CDCl.sub.3, 200
MHz): .delta. 2.03 (m, 4H), 2.66 (s, 3H), 3.29 (m, 4H), 5.12 (s,
2H), 6.84 (d, J=9.2 Hz, 1H), 7.07-6.97 (m, 3H), 7.40-7.33 (m, 5H),
7.98 (d, J=7.6 Hz, 1H), 8.01 (d, J=3.2 Hz, 1H), 8.78 (d, J=9.2 Hz,
1H), 12.15 (s, 1H); .sup.13C-NMR (CDCl.sub.3, 50 MHz) 203.62,
164.90, 162.20, 161.40, 143.38, 136.46, 130.93, 129.14, 128.66,
128.13, 127.92, 127.49, 123.11, 122.27, 118.68, 114.76, 113.23,
70.10, 47.95, 28.63, 25.42; Anal. Calcd for
C.sub.26H.sub.26N.sub.2O.sub.3; C, 75.34; H, 6.32; N, 6.76,
[0228] N-(2-Acetyl-4-dimethylaminophenyl)-4-(benzyloxy)benzamide
(100) was obtained from 62 and 85, using the same synthetic
procedure as for 92. The crude product was purified by column
chromatography (silica gel, CH.sub.2Cl.sub.2) to give 100 as yellow
solid. (1.7 g, 4.4 mmol); yield 65.0%; mp 139-140.degree. C.; MS
(EI, 70 eV): m/z 388.2 (M.sup.+); .sup.1H-NMR (CDCl.sub.3, 200
MHz): .delta. 2.66 (s, 3H), 2.94 (s, 6H), 5.10 (s, 2H), 7.00-7.06
(m, 3H), 7.17 (d, J=2.8 Hz, 1H), 7.33-7.44 (m, 5H), 7.97 (d, J=1.6
Hz, 1H), 8.00 (d, J=1.6 Hz, 1H), 8.80 (d, J=9.2 Hz, 1H), 12.19 (s,
1H); .sup.13C-NMR (CDCl.sub.3, 50 MHz) .delta.: 203.50, 165.00,
161.49, 145.80, 136.44, 132.21, 129.19, 128.66, 128.14, 127.78,
127.49, 122.91, 122.06, 120.06, 114.80, 70.11, 40.97, 28.60; Anal.
Calcd for C.sub.24H.sub.24N.sub.2O.sub.3; C, 74.21; H, 6.23; N,
7.21.
[0229]
N-(2-Acetyl-4-morpholinophenyl)-4-(benzyloxy)-3-methoxybenzamide
(101) was obtained from 60 and 86, using the same synthetic
procedure as for 92. The crude product was purified by column
chromatography (silica gel, CH.sub.2Cl.sub.2/n-hexane=5:1) to give
101 as yellow solid. (1.9 g, 4.1 mmol); yield 82.6%; mp
192-194.degree. C.; MS (EI, 70 eV): m/z 460.2 (M.sup.+);
.sup.1H-NMR (CDCl.sub.3, 200 MHz): .delta. 2.67 (s, 3H), 3.13 (m,
4H), 3.86 (m, 4H), 5.22 (s, 2H), 6.93 (d, J=8.4 Hz, 1H), 7.54 (dd,
J=9.2, 2.8 Hz, 1H), 7.30-7.45 (m, 6H), 7.54 (dd, J=8.4, 2.0 Hz,
1H), 7.61 (d, J=2.0 Hz, 1H), 8.84 (d, J=9.2 Hz, 1H), 12.15 (s, 1H);
.sup.13C-NMR (CDCl.sub.3, 50 MHz) .delta.: 203.09, 165.26, 151.16,
149.59, 136.52, 134.94, 128.65, 128.02, 127.90, 127.21, 123.58,
122.72, 121.90, 120.03, 118.43, 112.91, 111.14, 70.88, 66.77,
56.08, 49.95, 28.59; Anal. Calcd for
C.sub.22H.sub.28N.sub.2O.sub.5; C, 70.42; H, 6.13; N, 6.08.
[0230]
N-(2-Acetyl-4-pyrrolidinophenyl)-4-(benzyloxy)-3-methoxybenzamide
(102) was obtained from 61 and 86, using the same synthetic
procedure as for 92. The crude product was purified by column
chromatography (silica gel, CH.sub.2Cl.sub.2/n-hexane=3:1) to give
102 as yellow solid. (2.0 g, 4.5 mmol); yield 83.6%; mp
152-154.degree. C.; MS (EI, 70 eV): m/z 444.6 (M.sup.+);
.sup.1H-NMR (CDCl.sub.3, 200 MHz): .delta. 2.04 (m, 4H), 2.66 (s,
3H), 3.30 (m, 4H), 3.98 (s, 3H), 5.22 (s, 2H), 6.84 (dd, J=9.2, 2.8
Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 7.97 (m, 1H), 7.24-7.45 (m, 5H),
7.53 (dd, J=8.4, 2.0 Hz, 1H), 7.63 (d, J=2.0 Hz, 1H), 8.77 (d,
J=9.2 Hz, 1H), 12.17 (s, 1H); .sup.13C-NMR (CDCl.sub.3, 50 MHz)
203.09, 165.26, 151.16, 149.59, 136.52, 134.94, 128.65, 128.02,
127.90, 127.21, 123.58, 122.72, 121.90, 120.03, 118.43, 112.91,
111.14, 70.88, 66.77, 56.08, 49.95, 28.59; Anal. Calcd for
C.sub.27H.sub.28N.sub.2O.sub.4; C, 72.95; H, 6.35; N, 6.30.
[0231]
N-(2-Acetyl-4-morpholinophenyl)benzo[d][1,3]dioxole-4-carboxamide
(103) was obtained from 60 and 87, using the same synthetic
procedure as for 92. The crude product was purified by column
chromatography (silica gel, CHCl.sub.3/n-hexane=10:1) to give 103
as yellow solid. (1.06 g, 2.88 mmol); yield 79.3%; mp
150-152.degree. C.; MS (EI, 70 eV): m/z 368.5 (M.sup.+);
.sup.1H-NMR (CDCl.sub.3, 200 MHz): .delta. 2.62 (s, 3H), 3.15 (m,
4H), 3.89 (m, 4H), 6.17 (s, 2H), 6.90-6.96 (m, 2H), 7.50 (dd,
J=9.2, 2.8 Hz, 1H), 7.50 (dd, J=6.6, 2.8 Hz, 1H), 7.38 (m, 1H),
8.70 (d, J=9.2 Hz, 1H), 11.87 (s, 1H); .sup.13C-NMR (CDCl.sub.3, 50
MHz) .delta.: 2201.77, 162.60, 148.12, 145.80, 133.50, 124.69,
123.63, 122.57, 121.95, 121.78, 118.29, 116.95, 111.51, 101.79,
66.60, 50.07, 28.59; Anal. Calcd for
C.sub.20H.sub.20N.sub.2O.sub.5; C, 65.21; H, 5.47; N, 7.60.
[0232]
N-(2-Acetyl-4-pyrrolidinophenyl)benzo[d][1,3]dioxole-4-carboxamide
(104) was obtained from 61 and 87, using the same synthetic
procedure as for 92. The crude product was purified by column
chromatography (silica gel, CH.sub.2Cl.sub.2/n-hexane=8:1) to give
104 as yellow solid. (0.8 g, 2.3 mmol); yield 57.9%; mp
139-141.degree. C.; MS (EI, 70 eV): m/z 352.1 (M.sup.+);
.sup.1H-NMR (CDCl.sub.3, 200 MHz): .delta. 2.01 (m, 4H), 2.61 (s,
3H), 3.31 (m, 4H), 6.17 (s, 2H), 6.81-7.01 (m, 4H), 7.50 (dd,
J=6.2, 3.2 Hz, 1H), 8.60 (d, J=9.2 Hz, 1H), 11.87 (s, 1H);
.sup.13C-NMR (CDCl.sub.3, 50 MHz) .delta. 202.25, 162.21, 148.06,
145.67, 125.24, 124.01, 121.98, 121.68, 117.32, 111.22, 101.70,
48.37, 48.56, 25.38; Anal. Calcd for
C.sub.20H.sub.20N.sub.2O.sub.4; C, 68.17; H, 5.72; N, 7.95.
[0233] N-(2-Acetyl-4-morpholinophenyl)-2,3-dimethoxybenzamide (105)
was obtained from 60 and 88, using the same synthetic procedure as
for 92. The crude product was purified by column chromatography
(silica gel, CHCl.sub.3/n-hexane=10:1) to give 105 as yellow solid.
(1.5 g, 3.9 mmol); yield 78.2%; mp 146-148.degree. C.; MS (EI, 70
eV): ml: 384.5 (M.sup.+); .sup.1H-NMR (CDCl.sub.3, 200 MHz):
.delta. 2.61 (s, 3H), 3.15 (m, 4H), 3.87 (m, 4H), 3.99 (s, 3H),
4.05 (s, 3H), 6.99-7.62 (m, 5H), 8.78 (d, J=9.2 Hz, 1H), 12.15 (s,
1H); .sup.13C-NMR (CDCl.sub.3, 200 MHz) .delta. 201.30, 164.52,
152.94, 147.73, 146.29, 133.20, 128.39, 125.43, 124.01, 123.71,
122.50, 122.19, 117.98, 115.51, 66.67, 61.61, 56.09, 50.03, 28.58;
Anal. Calcd for C.sub.21H.sub.24N.sub.2O.sub.5; C, 65.61; H, 6.29;
N, 7.29.
[0234] N-(2-Acetyl-4-pyrrolidinophenyl)-2,3-dimethoxybenzamide
(106) was obtained from 61 and 88, using the same synthetic
procedure as for 92. The crude product was purified by column
chromatography (silica gel, CH.sub.2Cl.sub.2/n-hexane=10:1) to give
106 as yellow solid. (1.4 g, 3.8 mmol); yield 77.6%; mp
137-140.degree. C.; MS (EI, 70 eV): m/z 368.5 (M.sup.+);
.sup.1H-NMR (CDCl.sub.3, 200 MHz): .delta. 2.00 (m, 4H), 2.59 (s,
3H), 3.28 (m, 4H), 3.86 (s, 3H), 3.98 (s, 3H), 6.74 (m, 4H),
7.14-6.92 (m, 3H), 7.59 (dd, J=7.6, 1.8 Hz, 1H), 8.63 (d, J=9.0 Hz,
1H), 11.96 (s, 1H); .sup.13C-NMR (CDCl.sub.3, 50 MHz) .delta.:
201.83, 164.07, 152.92, 147.66, 143.71, 128.76, 125.96, 124.00,
123.94, 122.46, 117.32, 115.24, 112.79, 61.58, 56.08, 48.03, 28.59,
25.39; Anal. Calcd for C.sub.21H.sub.24N.sub.2O.sub.4; C, 68.46; H,
6.57; N, 7.60.
[0235] N-(2-Acetyl-4-morpholinophenyl)-2,5-dimethoxybenzamide (107)
was obtained from 60 and 89, using the same synthetic procedure as
for 92. The crude product was purified by column chromatography
(silica gel, CHCl.sub.3/EtOAc=8:1) to give 107 as yellow solid.
(1.67 g, 4.3 mmol); yield 79.7%; mp 172-174.degree. C.; MS (EI, 70
eV): ink: 384.5 (M.sup.+); .sup.1H-NMR (CDCl.sub.3, 200 MHz):
.delta. 2.61 (s, 3H), 3.15 (m, 4H), 3.80 (s, 3H), 3.87 (m, 4H),
4.07 (s, 3H), 6.95-7.32 (m, 4H), 7.73 (d, J=2.8 Hz, 1H), 8.78 (d,
J=9.2 Hz, 1H), 12.25 (s, 1H); .sup.13C-NMR (CDCl.sub.3, 50 MHz)
.delta. 201.21, 164.05, 153.63, 151.95, 146.52, 132.80, 125.75,
123.96, 122.95, 122.01, 119.69, 117.66, 115.69, 112.79, 66.79,
56.12, 55.83, 49.86, 28.76; Anal. Calcd for
C.sub.21H.sub.24N.sub.2O.sub.5; C, 65.61; H, 6.29; N, 7.29.
[0236] N-(2-Acetyl-4-pyrrolidinophenyl)-2,5-dimethoxybenzamide
(108) was obtained from 61 and 89, using the same synthetic
procedure as for 92. The crude product was purified by column
chromatography (silica gel, CH.sub.2Cl.sub.2/n-hexane=8:1) to give
108 as yellow solid. (1.6 g, 4.3 mmol); yield 73.8%; mp
137-140.degree. C.; MS (EI, 70 eV): m/z 368.5 (M''); .sup.1H-NMR
(CDCl.sub.3, 200 MHz): .delta. 2.01 (m, 4H), 2.60 (s, 3H), 3.29 (m,
4H), 3.80 (s, 3H), 4.06 (s, 3H), 6.77 (dd, J=9.2, 3.0 Hz, 1H),
6.89-6.97 (m, 3H), 7.74 (d, J=2.8 Hz, 1H), 8.64 (d, =9.2 Hz, 1H),
12.08 (s, 1H); .sup.13C-NMR (CDCl.sub.3, 200 MHz) .delta. 201.75,
163.61, 153.61, 151.91, 143.69, 128.64, 126.30, 124.32, 123.30,
119.36, 117.20, 115.62, 112.78, 56.15, 55.83, 47.94, 28.77, 25.42;
Anal. Calcd for C.sub.21H.sub.24N.sub.2O.sub.4; C, 68.46; H, 6.57;
N, 7.60.
[0237] N-(2-Acetyl-4-morpholinophenyl)-2-methoxybenzamide (109) was
obtained from 60 and 90, using the same synthetic procedure as for
92. The crude product was purified by column chromatography (silica
gel, CH.sub.2Cl.sub.2/n-hexane=10:1) to give 109 as yellow solid.
(1.4 g, 3.9 mmol); yield 72.6%; mp 158-160.degree. C.; MS (EI, 70
eV): m/z 354.5 (M.sup.+); .sup.1H-NMR (CDCl.sub.3, 200 MHz):
.delta. 2.60 (s, 3H), 3.12 (m, 4H), 3.85 (m, 4H), 4.09 (s, 3H),
6.96-7.07 (m, 2H), 7.13 (dd, J=9.2, 3:0 Hz, 1H), 7.34-7.43 (m, 2H),
8.14 (dd, J=7.6, 1.8 Hz, 1H), 8.80 (d, J=9.2 Hz, 1H), 12.23 (s,
1H); .sup.13C-NMR (CDCl.sub.3, 50 MHz) .delta. 201.25, 164.33,
157.56, 146.18, 133.01, 132.25, 125.46, 123.83, 122.63, 122.18,
120.89, 117.92, 111.31, 66.69, 55.58, 49.98, 28.76; Anal. Calcd for
C.sub.20H.sub.22N.sub.2O.sub.4; C, 67.78; H, 6.26; N, 7.90.
[0238] N-(2-Acetyl-4-pyrrolidinophenyl)-2-methoxybenzamide (110)
was obtained from 61 and 90, using the same synthetic procedure as
for 92. The crude product was purified by column chromatography
(silica gel, CH.sub.2Cl.sub.2) to give 110 as yellow solid. (1.1 g,
3.3 mmol); yield 83.1%; mp 168-170.degree. C.; MS (EI, 70 eV): m/z.
338.5 (M.sup.+); .sup.1H-NMR (CDCl.sub.3, 200 MHz): .delta. 1.96
(m, 4H), 2.64 (s, 3H), 3.27 (m, 4H), 4.05 (s, 3H), 6.81 (dd, J=9.0,
2.6 Hz, 1H), 7.00-7.53 (m, 4H), 7.96 (dd, J=7.8, 1.8 Hz, 1H), 8.50
(d, J=9.0 Hz, 1H), 11.87 (s, 1H); .sup.13C-NMR (CDCl.sub.3, 50 MHz)
.delta. 202.81, 163.21, 157.44, 144.08, 133.51, 131.70, 127.89,
126.64, 123.70, 122.76, 121.13, 117.04, 113.42, 112.51, 56.17,
47.94, 29.37, 25.38; Anal. Calcd for
C.sub.20H.sub.22N.sub.2O.sub.3; C, 70.99; H, 6.55; N, 8.28.
[0239] N-(2-Acetyl-4-morpholinophenyl)-2-methoxybenzamide (111) was
obtained from 60 and 91, using the same synthetic procedure as for
92. The crude product was purified by column chromatography (silica
gel, CH.sub.2Cl.sub.2/EtOAc=15:1) to give 111 as yellow solid. (1.1
g, 3.1 mmol); yield 76.0%; mp 185-187.degree. C.; MS (EI, 70 eV):
m/z 354.5 (M.sup.+); .sup.1H-NMR (CDCl.sub.3, 200 MHz): .delta.
2.67 (s, 3H), 3.13 (m, 4H), 3.84 (s, 3H), 3.86 (m, 4H), 6.95 (d,
J=2.0 Hz, 1H), 6.98 (d, J=2.0 Hz, 1H), 7.21 (dd, J=9.2, 2.8 Hz,
1H), 7.38 (d, J=2.8 Hz, 1H), 7.97 (d, J=2.0 Hz, 1H), 8.00 (d, J=2.0
Hz, 1H), 8.85 (d, J=9.2 Hz, 1H), 12.29 (s, 1H); .sup.13C-NMR
(CDCl.sub.3, 50 MHz) .delta. 203.11, 165.30, 162.48, 146.21,
135.01, 1229.24, 127.29, 123.61, 122.72, 121.99, 118.39, 113.95,
66.78, 55.42, 49.95, 28.61; Anal. Calcd for
C.sub.20H.sub.22N.sub.2O.sub.4; C, 67.78; H, 6.26; N, 7.90.
[0240] N-(2-Acetyl-4-pyrrolidinophenyl)-4-methoxybenzamide (112)
was obtained from 61 and 91, using the same synthetic procedure as
for 92. The crude product was purified by column chromatography
(silica gel, CH.sub.2Cl.sub.2/n-hexane=10:1) to give 112 as yellow
solid. (1.2 g, 3.5 mmol); yield 72.5%; mp 174-175.degree. C.; MS
(EI, 70 eV): m/z 338.5 (M.sup.+); .sup.1H-NMR (CDCl.sub.3, 200
MHz): CH.sub.2Cl.sub.2/n-hexane=10:1; NMR (CDCl.sub.3, 50 MHz)
.delta. 203.60, 164.95, 162.25, 143.27, 132.19, 129.12, 127.67,
123.10, 122.24, 118.74, 113.87, 55.39, 48.02, 28.60, 25.38; Anal.
Calcd for C.sub.20H.sub.22N.sub.2O.sub.3; C, 70.99; H, 6.55; N,
8.28.
[0241] 2-(2-Benzyloxyphenyl)-6-morpholinoquinolin-4-one (113). To a
solution of 92 (1.2 g, 2.7 mmol) in 1,4 dioxane (150 ml) was added
NaOH (0.9 g, 21.4 mmol). The mixture was refluxed for 5 h,
concentrated and added 10% NH.sub.4Cl (100 ml). The precipitate was
collected and washed with H.sub.2O and acetone. The crude product
was purified by column chromatography (silica gel,
CHCl.sub.3:MeOH=25:1) to give 113 as yellow solid (1.3 g, 3.2
mmol). Yield: 65.4%; mp 281-283.degree. C.; MS (EI, 70 eV): m/z
412.4 (M.sup.+); .sup.1H-NMR (DMSO-d.sub.6. 200 MHz): .delta. 3.15
(m, 4H), 3.77 (m, 4H), 5.12 (s, 2H), 6.30 (s, 1H), 7.36-7.50 (m,
11H), 7.66 (d, J=9.2 Hz, 1H), 11.57 (s, 1H); Anal. Calcd for
C.sub.26H.sub.24N.sub.2O.sub.3; C, 75.71; H, 5.86; N, 6.79.
[0242] 2-(2-Benzyloxyphenyl)-6-pyrrolidinoquinolin-4-one (114) was
obtained from 93, using the same synthetic procedure as for 113.
The crude product was purified by column chromatography (silica
gel, CHCl.sub.3:MeOH=25:1) to give 114 as yellow solid. (0.7 g, 1.8
mmol). Yield: 61.1%; mp 293-295.degree. C.; MS (EI, 70 eV): m/z
396.4 (M.sup.+); .sup.1H-NMR (DMSO-d.sub.6, 200 MHz): .delta. 1.99
(m, 4H), 3.34 (m, 4H), 5.21 (s, 2H), 6.33 (s, 1H), 7.00-7.50 (m,
1H), 7.68 (d, J=9.0 Hz, 1H), 11.63 (s, 1H); Anal. Calcd for
C.sub.26H.sub.24N.sub.2O.sub.2; C, 78.76; H, 6.10; N, 7.07.
[0243] 2-(2-Benzyloxyphenyl)-6-dimethylaminoquinolin-4-one (115)
was obtained from 94, using the same synthetic procedure as for
113. The crude product was purified by column chromatography
(silica gel, CHCl.sub.3:MeOH=25:1) to give 115 as yellow solid.
(1.2 g, 1.8 mmol). Yield: 61.1%; mp 210-212.degree. C.; MS (EI, 70
eV): m/z 370.2 (M.sup.+); .sup.1H-NMR (DMSO-d.sub.6, 200 MHz):
.delta. 2.91 (s, 6H), 5.13 (s, 2H), 6.02 (s, 1H), 7.07 (t, J=7.4
Hz, 1H), 7.17 (d, J=2.6 Hz, 1H), 7.22-7.48 (m, 9H), 7.53 (d, J=9.2
Hz, 1H), 11.67 (s, 1H); Anal. Calcd for
C.sub.24H.sub.22N.sub.2O.sub.2; C, 77.81; H, 5.99; N, 7.56.
[0244] 2-(3-Benzyloxyphenyl)-6-morpholinoquinolin-4-one (116) was
obtained from 95, using the same synthetic procedure as for 113.
The crude product was purified by column chromatography (silica
gel, CHCl.sub.3:MeOH=25:1) to give 116 as yellow solid. (0.8 g, 1.9
mmol). Yield: 61.1%; mp 283-285.degree. C.; MS (EI, 70 eV): m/z
412.4 (M.sup.+); .sup.1H-NMR (DMSO-d.sub.6, 200 MHz): .delta. 3.15
(m, 4H), 3.77 (m, 4H), 5.12 (s, 2H), 6.30 (s, 1H), 7.36-7.50 (m,
11H), 7.66 (d, J=9.2 Hz, 1H), 11.57 (s, 1H); Anal. Calcd for
C.sub.26H.sub.24N.sub.2O.sub.3; C, 75.71; H, 5.86; N, 6.79.
[0245] 2-(3-Benzyloxyphenyl)-6-pyrrolidinoquinolin-4-one (117) was
obtained from 96, using the same synthetic procedure as for 113.
The crude product was purified by column chromatography (silica
gel, CHCl.sub.3:MeOH=25:1) to give 117 as yellow solid. (0.38 g,
0.95 mmol). Yield: 66.3%; mp 320-322.degree. C.; MS (EI, 70 eV):
m/z 396.4 (M.sup.+); .sup.1H-NMR (DMSO-d.sub.6, 200 MHz): .delta.
2.07 (m, 4H), 3.34 (m, 4H), 5.21 (s, 2H), 6.35 (s, 1H), 6.87-7.49
(m, 10H), 7.70 (d, J=9.0 Hz, 1H), 7.78 (d, J=8.6 Hz, 1H), 11.50 (s,
1H); Anal. Calcd for C.sub.26H.sub.24N.sub.2O.sub.2; C, 78.76; H,
6.10; N, 7.07.
[0246] 2-(3-Benzyloxyphenyl)-6-dimethylaminoquinolin-4-one (118)
was obtained from 97, using the same synthetic procedure as for
113. The crude product was purified by column chromatography
(silica gel, CHCl.sub.3:MeOH=25:1) to give 118 as yellow solid.
(1.3 g, 3.5 mmol). Yield: 65.6%; mp 307-308.degree. C.; MS (EI, 70
eV): m/z 370.2 (M.sup.+); .sup.1H-NMR (DMSO-d.sub.6, 200 MHz):
.delta. 2.91 (s, 6H), 5.13 (s, 2H), 6.02 (s, 1H), 7.07 (t, J=7.4
Hz, 1H), 7.17 (d, J=2.6 Hz, 1H), 7.22-7.48 (m, 9H), 7.53 (d, J=9.2
Hz, 1H), 11.67 (s, 1H); Anal. Calcd for
C.sub.24H.sub.22N.sub.2O.sub.2; C, 77.81; H, 5.99; N, 7.56.
[0247] 2-(4-Benzyloxyphenyl)-6-morpholinoquinolin-4-one (119) was
obtained from 98, using the same synthetic procedure as for 113.
The crude product was purified by column chromatography (silica
gel, CHCl.sub.3:MeOH=25:1) to give 119 as yellow solid. (0.5 g, 1.2
mmol). Yield: 52.2%; mp 320-323.degree. C.; MS (EI, 70 eV): m/z
412.4 (M.sup.+); .sup.1H-NMR (DMSO-d.sub.6, 200 MHz): .delta. 3.14
(m, 4H), 3.77 (m, 4H), 5.21 (s, 2H), 6.24 (s, 1H), 7.16-7.49 (m,
9H), 7.66 (d, J=9.0 Hz, 1H), 7.76 (d, J=8.6 Hz, 1H), 11.48 (s, 1H);
Anal. Calcd for C.sub.26H.sub.24N.sub.2O.sub.3; C, 75.71; H, 5.86;
N, 6.79.
[0248] 2-(4-Benzyloxyphenyl)-6-pyrrolidinoquinolin-4-one (120) was
obtained from 99, using the same synthetic procedure as for 113.
The crude product was purified by column chromatography (silica
gel, CHCl.sub.3:MeOH=25:1) to give 120 as yellow solid. (0.6 g, 1.5
mmol). Yield: 57.5%; mp 330-332.degree. C.; MS (EI, 70 eV): m/z
396.2 (M.sup.+); .sup.1H-NMR (DMSO-d.sub.o, 200 MHz): .delta. 1.99
(m, 4H), 3.34 (m, 4H), 5.21 (s, 2H), 6.33 (s, 1H), 7.00-7.50 (m,
11H), 7.68 (d, J=9.0 Hz, 1H), 11.63 (s, 1H); Anal. Calcd for
C.sub.26H.sub.24N.sub.2O.sub.2; C, 78.76; H, 6.10; N, 7.07.
[0249] 2-(4-Benzyloxyphenyl)-6-dimethylaminoquinolin-4-one (121)
was obtained from 100, using the same synthetic procedure as for
113. The crude product was purified by column chromatography
(silica gel, CHCl.sub.3:MeOH=25:1) to give 121 as yellow solid.
(1.2 g, 3.2 mmol). Yield: 78.7%; mp 283-285.degree. C.; MS (EI, 70
eV): m/z 370.2 (M.sup.+); .sup.1H-NMR (DMSO-d.sub.6, 200 MHz):
.delta. 2.92 (s, 6H), 5.17 (s, 2H), 6.17 (s, 1H), 7.14 (d, J=8.6
Hz, 2H), 7.24 (dd, J=8.8, 2.4 Hz, 1H), 7.29-7.46 (m, 6H), 7.53 (d,
J=9.0 Hz, 1H), 7.73 (d, J=8.6 Hz, 2H), 11.38 (s, 1H); Anal. Calcd
for C.sub.24H.sub.22N.sub.2O.sub.2; C, 77.81; N, 7.56.
[0250] 2-(4-(Benzyloxy)-3-methoxyphenyl)-6-morpholinoquinolin-4-one
(122) was obtained from 101, using the same synthetic procedure as
for 113. The crude product was purified by column chromatography
(silica gel, CHCl.sub.3:MeOH=25:1) to give 122 as yellow solid.
(0.5 g, 1.1 mmol). Yield: 52.1%; nip 300-301.degree. C.; MS (EI, 70
eV): m/z 442.2 (M.sup.+); .sup.1H-NMR (DMSO-d.sub.6. 200 MHz):
.delta. 3.11 (m, 4H), 3.74 (m, 4H), 5.15 (s, 2H), 6.28 (s, 1H),
7.16 (d, J=8.2 Hz, 2H), 7.25-7.45 (m, 9H), 7.68 (d, J=9.0 Hz, 1H),
11.48 (br, 1H); Anal. Calcd for C.sub.27H.sub.26N.sub.2O.sub.4; C,
72.28; H, 5.92; N, 6.23.
[0251]
2-(4-(Benzyloxy)-3-methoxyphenyl)-6-pyrrolidinoquinolin-4-one (123)
was obtained from 102, using the same synthetic procedure as for
113. The crude product was purified by column chromatography
(silica gel, CHCl.sub.3:MeOH=25:1) to give 123 as yellow solid.
(1.3 g, 3.1 mmol). Yield: 65.2%; mp 304-306.degree. C.; MS (EI, 70
eV): m/z 426.6 (M.sup.+); .sup.1H-NMR (DMSO-d.sub.6, 200 MHz):
.delta. 1.99 (m, 4H), 3.33 (m, 4H), 3.89 (s, 3H), 5.18 (s, 2H),
6.25 (s, 1H), 7.02-7.09 (m, 2H), 7.19 (d, J=8.2 Hz, 1H), 7.33-7.45
(m, 2H), 7.64 (d, J=8.8 Hz, 1H), 11.34 (s, 1H); Anal. Calcd for
C.sub.27H.sub.26N.sub.2O.sub.3; C, 76.03; H, 6.14; N, 6.57.
[0252] 2-(Benzo[d][1,3]-dioxol-4-yl)-6-morpholinoquinolin-4-one
(124) was obtained from 103, using the same synthetic procedure as
for 113. The crude product was purified by column chromatography
(silica gel, CHCl.sub.3:MeOH=25:1) to give 124 as yellow solid.
(0.5 g, 1.4 mmol). Yield: 52.6%; mp 350-352.degree. C.; MS (EI, 70
eV): m/z 350.5 (M.sup.+); .sup.1H-NMR (DMSO-d.sub.6, 200 MHz):
.delta. 3.16 (m, 4H), 3.77 (m, 4H), 6.15 (s, 2H), 6.43 (s, 1H),
7.04 (d, J=7.8 Hz, 1H), 7.09 (dd, J=7.8, 1.8 Hz, 1H), 7.28 (d,
J=7.0 Hz, 1H), 7.40 (d, J=2.8 Hz, 1H), 7.50 (dd, J=9.2, 2.8 Hz,
1H), 7.67 (d, J=9.2 Hz, 1H), 11.54 (s, 1H); Anal. Calcd for
C.sub.20H.sub.18N.sub.2O.sub.4; C, 68.56; H, 5.18; N, 8.00.
[0253] 2-(Benzo[d][1,3]-dioxol-4-yl)-6-pyrrolidinoquinolin-4-one
(125) was obtained from 104, using the same synthetic procedure as
for 113. The crude product was purified by column chromatography
(silica gel, CHCl.sub.3:MeOH=25:1) to give 125 as yellow solid.
(0.2 g, 0.6 mmol). Yield: 52.6%; mp 330-332.degree. C.; MS (EI, 70
eV): m/z 334.4 (M.sup.+); .sup.1H-NMR (DMSO-d.sub.6, 200 MHz):
.delta. 1.95 (m, 3.16 (m, 4H), 6.11 (s, 2H), 6.25 (s, 1H),
6.96-7.06 (m, 2H), 7.19 (d, J=6.8 Hz, 1H), 7.57 (d, J=9.0 Hz, 1H),
11.39 (s, 1H); Anal. Calcd for C.sub.20H.sub.18N.sub.2O.sub.3; C,
71.84; H, 5.43; N, 8.38.
[0254] 2-(2,3-Dimethoxyphenyl)-6-morpholinoquinolin-4-one (126) was
obtained from 105, using the same synthetic procedure as for 113.
The crude product was purified by column chromatography (silica
gel, CHCl.sub.3:MeOH=25:1) to give 126 as yellow solid. (0.5 g, 1.4
mmol). Yield: 52.5%; mp 235-236.degree. C.; MS (EI, 70 eV): ml:
366.5 (M.sup.+); (DMSO-d.sub.6, 200 MHz): .delta. 3.11 (m, 4H),
3.60 (s, 3H), 3.83 (m, 4H), 3.96 (s, 3H), 5.98 (s, 1H), 6.96-7.447
(m, 5H), 7.54 (d, J=9.6 Hz, 1H), 11.63 (s, 1H); .sup.13C-NMR
(DMSO-d.sub.6, 50 MHz) .delta. 176.63, 153.13, 147.90, 147.02,
146.66, 134.72, 129.90, 126.00, 124.84, 123.01, 121.98, 119.96,
114.93, 108.72, 107.52, 66.53, 61.13, 56.43, 49.47; Anal. Calcd for
C.sub.21H.sub.22N.sub.2O.sub.4; C, 68.84; H, 6.05; N, 7.65.
[0255] 2-(2,3-Dimethoxyphenyl)-6-pyrrolidinoquinolin-4-one (127)
was obtained from 106, using the same synthetic procedure as for
113. The crude product was purified by column chromatography
(silica gel, CHCl.sub.3:MeOH=25:1) to give 127 as yellow solid.
(0.3 g, 0.9 mmol). Yield: 52.5%; mp 258-260.degree. C.; MS (EI, 70
eV): m/z 350.5 (M.sup.+); .sup.1H-NMR (DMSO-d.sub.6, 200 MHz):
.delta. 1.95 (m, 4H), 3.23 (m, 4H), 3.60 (s, 3H), 3.84 (s, 3H),
5.92 (s, 1H), 6.97-7.19 (m, 5H), 7.54 (d, f=8.4 Hz, 1H), 11.48 (s,
1H); .sup.13C-NMR (DMSO-d.sub.6, 50 MHz) .delta. 176.49, 153.13,
146.67, 146.07, 144.85, 132.16, 126.71, 124.78, 122.02, 119.99,
119.12, 114.77, 107.83, 103.18, 61.10, 56.43, 48.11, 25.44; Anal.
Calcd for C.sub.21H.sub.22N.sub.2O.sub.3; C, 71.98; H, 6.33; N,
7.99.
[0256] 2-(2,5-Dimethoxyphenyl)-6-morpholinoquinolin-4-one (128) was
obtained from 107, using the same synthetic procedure as for 113.
The crude product was purified by column chromatography (silica
gel, CHCl.sub.3:MeOH=25:1) to give 128 as yellow solid. (0.7 g, 1.9
mmol). Yield: 61.2%; nip 275-277.degree. C.; MS (EI, 70 eV): m/z
366.2 (M.sup.+); .sup.1H-NMR (DMSO-d.sub.6, 200 MHz): .delta. 3.14
(m, 4H), 3.75 (m, 10H), 6.03 (s, 1H), 7.03-7.49 (m, 5H), 7.67 (d,
J=9.0 Hz, 1H), 11.57 (s, 1H); .sup.13C-NMR (DMSO-d.sub.6, 50 MHz)
.delta. 176.67, 153.49, 150.98, 147.80, 147.00, 134.68, 125.97,
124.87, 122.89, 119.92, 116.57, 113.71, 108.93, 107.46, 66.53,
56.64, 49.45; Anal. Calcd for C.sub.21H.sub.22N.sub.2O.sub.4; C,
68.84; H, 6.05; N, 7.65.
[0257] 2-(2,5-Dimethoxyphenyl)-6-pyrrolidinoquinolin-4-one (129)
was obtained from 108, using the same synthetic procedure as for
113. The crude product was purified by column chromatography
(silica gel, CHCl.sub.3:MeOH=25:1) to give 129 as yellow solid.
(0.9 g, 0.9 mmol). Yield: 59.2%; mp 272-274.degree. C.; MS (EI, 70
eV): m/z 350.2 (10; IR (KBr): 1606.77 (C.dbd.O), 2978.22 (--NH)
cm.sup.-1, .sup.1H-NMR (DMSO-d.sub.6, 200 MHz): .delta. 1.95 (m,
4H), 3.25 (m, 4H), 3.71 (s, 3H), 3.72 (s, 3H), 5.94 (s, 2H),
6.99-7.11 (m, 5H), 7.49 (d, J=8.6 Hz, 1H), 11.43 (s, 1H); Anal.
Calcd for C.sub.21H.sub.22N.sub.2O.sub.3; C, 71.98; H, 6.33; N,
7.99.
[0258] 2-(2-Methoxyphenyl)-6-morpholinoquinolin-4-one (130) was
obtained from 109, using the same synthetic procedure as for 113.
The crude product was purified by column chromatography (silica
gel, CHCl.sub.3:MeOH=25:1) to give 130 as yellow solid. (0.6 g, 1.8
mmol). Yield: 57.5%; mp 262-264.degree. C.; MS (EI, 70 eV): m/z
336.5 (M.sup.+); .sup.1H-NMR (DMSO-d.sub.6, 200 MHz): .delta. 3.10
(m, 4H), 3.74 (m, 4H), 3.76 (s, 3H), 5.97 (s, 1H); 7.05 (d, J=7.6
Hz, 1H), 7.16 (d, J=8.2 Hz, 1H), 7.40-7.54 (m, 5H), 11.55 (s, 1H);
.sup.13C-NMR (DMSO-d.sub.6, 50 MHz) .delta. 176.61, 156.96, 147.79,
147.42, 134.82, 131.73, 130.69, 125.89, 124.39, 122.89, 121.06,
119.97, 112.34, 108.85, 107.44, 66.54, 56.16, 49.48; Anal. Calcd
for C.sub.20H.sub.20N.sub.2O.sub.3; C, 71.41; H, 5.99; N, 8.33.
[0259] 2-(2-Methoxyphenyl)-6-pyrrolidinoquinolin-4-one (131) was
obtained from 110, using the same synthetic procedure as for 113.
The crude product was purified by column chromatography (silica
gel, CHCl.sub.3:MeOH=25:1) to give 131 as yellow solid. (0.7 g, 2.2
mmol). Yield: 62.3%; mp 312-313.degree. C.; MS (EI, 70 eV):
m1:320.2 (M.sup.+); .sup.1H-NMR (DMSO-d.sub.6, 200 MHz): .delta.
1.98 (m, 4H), 3.25 (m, 4H), 3.77 (s, 3H), 5.91 (s, 1H), 7.00-7.51
(m, 7H), 11.43 (s, 1H); .sup.13C-NMR (DMSO-d.sub.6, 50 MHz) .delta.
176.58, 156.97, 146.43, 144.75, 132.13, 131.60, 130.69, 126.65,
124.53, 121.04, 119.93, 119.05, 112.33, 108.03, 103.16, 56.15,
48.09, 25.45; Anal. Calcd for C.sub.20H.sub.20N.sub.2O.sub.2; C,
74.98; H, 6.29; N, 8.74.
[0260] 2-(4-Methoxyphenyl)-6-morpholinoquinolin-4-one (132) was
obtained from 111, using the same synthetic procedure as for 113.
The crude product was purified by column chromatography (silica
gel, CHCl.sub.3:MeOH=25:1) to give 132 as yellow solid. (0.5 g, 1.8
mmol). Yield: 65.9%; mp 302-304.degree. C.; MS (EI, 70 eV): m/z
336.2 (M); .sup.1H-NMR (DMSO-d.sub.6, 200 MHz): .delta. 3.10 (m,
4H), 3.74 (m, 4H), 3.80 (s, 3H), 6.22 (s, 1H), 7.06 (d, J=8.8 Hz,
2H), 7.38 (d, J=2.4 Hz, 1H), 7.43 (dd, J=9.2, 2.8 Hz, 1H), 7.64 (d,
J=9.2 Hz, 1H), 7.74 (d, J=8.8 Hz, 2H), 11.45 (s, 1H); Anal. Calcd
for C.sub.20H.sub.20N.sub.2O.sub.3; C, 71.41; H, 5.99; N, 8.33.
[0261] 2-(4-Methoxyphenyl)-6-pyrrolidinoquinolin-4-one (133) was
obtained from 112, using the same synthetic procedure as for 113.
The crude product was purified by column chromatography (silica
gel, CHCl.sub.3:MeOH=25: I) to give 133 as yellow solid. (0.4 g,
1.2 mmol). Yield: 74.0%; mp 312-313.degree. C.; MS (EI, 70 eV): m/z
320.2 (M.sup.+); Anal. Calcd for C.sub.20H.sub.20N.sub.2O.sub.2; C,
74.98; H, 6.29; N, 8.74.
[0262] 2-(2-Hydroxyphenyl)-6-morpholinoquinolin-4-one (134). To a
suspension of 113 (0.4 g, 1.0 mmol) in MeOH (400 ml) was
hydrogenated in the presence of 10% Pd/C (0.1 g) at 25.degree. for
3 h. The catalyst was filtered off and the filtrate was evaporated.
The crude product was purified by column chromatography (SiO.sub.2,
CHCl.sub.3:MeOH=25:1) to give 134 as yellow solid. (0.3 g, 0.9
mmol). Yield: 81.5%; mp 290-291.degree. C.; MS (EI, 70 eV): m/z
322.2 (M.sup.+); IR (KBr): 1612.56 (C.dbd.O), 2969.54 (--NH)
cm.sup.-1; .sup.1H-NMR (MeOD-d.sub.4, 400 MHz) .delta. 3.30 (m,
4H), 3.87 (m, 4H), 4.48 (s, 1H), 6.64 (s, 1H), 7.02 (d, J=8.8 Hz,
1H), 7.04 (d, J=8.8 Hz, 1H); 7.40 (t, J=8.0 Hz, 1H), 7.60 (d, J=8.8
Hz, 2H), 7.65 (d, J=2.0 Hz, 1H), 7.72 (d, J=9.2 Hz, 1H); Anal.
Calcd for C.sub.19H.sub.18N.sub.2O.sub.3; C, 70.79; H, 5.63; N,
8.69.
[0263] 2-(2-Hydroxyphenyl)-6-pyrrolidinoquinolin-4-one (135) was
obtained from 114, using the same synthetic procedure as for 134.
The crude product was purified by column chromatography (silica
gel, CHCl.sub.3:MeOH=25:1) to give 135 as yellow solid. (0.2 g, 0.7
mmol). Yield: 86.6%; mp 304-306.degree. C.; MS (EI, 70 eV): m/z
306.2 (M.sup.+); IR (KBr): 1612.56 (C.dbd.O), 2969.54 (--NH)
cm.sup.-1; .sup.1H-NMR (MeOD-d.sub.4. 400 MHz): .delta. 3.25 (m,
4H), 3.87 (m, 4H), 6.29 (s, 1H), 6.87 (d, J=3.2 Hz, 1H), 6.91 (dd,
J=8.8, 3.2 Hz, 1H), 7.03 (d, J=8.8 Hz, 1H), 7.45 (d, J=2.8 Hz, 1H),
7.48 (dd, J=9.2, 2.8 Hz, 1H), 7.61 (d, J=9.2 Hz, 1H), 9.45 (hr,
1H), 11.72 (hr, 1H); Anal. Calcd for
C.sub.19H.sub.18N.sub.2O.sub.2; C, 74.49; H, 5.92; N, 9.14.
[0264] 2-(2-Hydroxyphenyl)-6-dimethylaminoquinolin-4-one (136) was
obtained from 115, using the same synthetic procedure as for 134.
The crude product was purified by column chromatography (silica
gel, CHCl.sub.3:MeOH=25:1) to give 136 as yellow solid. Yield:
86.6%; mp 296-298.degree. C.; MS (EI, 70 eV): inlz 280.1 (M.sup.+);
IR (KBr): 1597.13 (C.dbd.O), 2908.78 (--NH) cm.sup.-1; .sup.1H-NMR
(MeOD-d.sub.4, 200 MHz) .delta. 3.02 (s, 6H), 6.56 (s, 1H),
6.92-6.99 (m, 2H), 7.27-7.38 (m, 3H), 7.50 (dd, J=8.2, 1.8 Hz, 1H),
7.60 (d, J=8.2 Hz, 1H); Anal. Calcd for
C.sub.17H.sub.16N.sub.2O.sub.2; C, 72.84; H, 5.75; N, 9.99.
[0265] 2-(3-Hydroxyphenyl)-6-morpholinoquinolin-4-one (137) was
obtained from 116, using the same synthetic procedure as for 134.
The crude product was purified by column chromatography (silica
gel, CHCl.sub.3:MeOH=25:1) to give 81a as yellow solid. (0.3 g, 0.9
mmol). Yield: 89.7%; mp 357-360.degree. C.; MS (EI, 70 eV): m/z
322.2 (M.sup.+); .sup.1H-NMR (DMSO-d.sub.6, 200 MHz) .delta. 3.13
(m, 4H), 3.75 (m, 4H), 6.20 (s, 1H), 6.81 (d, J=7.8 Hz, 1H),
7.15-7.22 (m, 2H), 7.33 (d, J=7.8 Hz, 1H), 7.43 (d, J=2.6 Hz, 1H),
7.48 (dd, J=9.0, 2.6 Hz, 1H), 7.69 (d, J=9.0 Hz, 1H), 9.86 (s, 1H),
11.56 (s, 1H); .sup.13C-NMR (DMSO-d.sub.6, 50 MHz) .delta. 176.78,
158.20, 149.47, 147.95, 136.28, 134.96, 130.59, 125.97, 122.95,
120.39, 118.36, 117.63, 114.38, 107.24, 106.22, 66.52, 49.32,
43.47; Anal. Calcd for C.sub.19H.sub.18N.sub.2O.sub.3; C, 70.79; H,
5.63; N, 8.69.
[0266] 2-(3-Hydroxyphenyl)-6-pyrrolidinoquinolin-4-one (138) was
obtained from 117, using the same synthetic procedure as for 134.
The crude product was purified by column chromatography (silica
gel, CHCl.sub.3:MeOH=25:1) to give 138 as yellow solid. (0.14 g,
0.45 mmol). Yield: 90.9%; mp 364-367.degree. C.; MS (EI, 70 eV):
rnlz 306.3 (M.sup.+); .sup.1H-NMR (DMSO-d.sub.6, 200 MHz) .delta.
1.80 (m, 4H), 3.29 (m, 4H), 6.14 (s, 1H), 6.92 (d, J=7.0 Hz, 1H),
7.02 (d, J=7.0 Hz, 1H), 7.09 (dd, J=9.2, 2.4 Hz, 1H), 7.15-7.21 (m,
2H), 7.34 (t, J=7.8 Hz, 1H), 7.65 (d, J=9.2 Hz, 1H), 9.84 (s, 1H),
11.46 (s, 1H); .sup.13C-NMR (DMSO-d.sub.6, 50 MHz) .delta. 176.78,
158.20, 149.47, 147.95, 136.28, 134.96, 130.59, 125.97, 122.95,
120.39, 118.36, 117.63, 114.38, 107.24, 106.22, 66.52, 49.32,
43.47; Anal. Calcd for C.sub.19H.sub.18N.sub.2O.sub.2; C, 74.49; H,
5.92; N, 9.14.
[0267] 2-(3-Hydroxyphenyl)-6-dimethylaminoquinolin-4-one (139) was
obtained from 118, using the same synthetic procedure as for 134.
The crude product was purified by column chromatography (silica
gel, CHCl.sub.3:MeOH=25:1) to give 139 as yellow solid. (0.4 g, 1.4
mmol). Yield: 75.6%; mp 342-344.degree. C.; MS (EI, 70 eV): ink:
280.1 (M); .sup.1H-NMR (DMSO-d.sub.6, 200 MHz) .delta. 2.93 (s,
6H), 6.23 (s, 1H), 6.92 (d, J=8.0 Hz, 1H), 7.16-7.35 (m, 6H), 7.70
(d, J=9.2 Hz, 1H), 9.93 (s, 1H), 11.46 (s, 1H); .sup.13C-NMR
(DMSO-d.sub.6, 50 MHz) .delta. 175.86, 158.25, 148.99, 147.63,
136.34, 133.33, 130.52, 126.09, 120.64, 120.22, 118.32, 117.58,
114.39, 105.55, 103.94, 38.69; Anal. Calcd for
C.sub.17H.sub.16N.sub.2O.sub.2; C, 72.84; H, 5.75; N, 9.99.
[0268] 2-(4-Hydroxyphenyl)-6-morpholinoquinolin-4-one (140) was
obtained from 119, using the same synthetic procedure as for 134.
The crude product was purified by column chromatography (silica
gel, CHCl.sub.3:MeOH=25:1) to give 140 as yellow solid. (0.1 g, 0.3
mmol). Yield: 64.5%; mp 340-342.degree. C.; MS (EI, 70 eV): m/z
322.2 (M.sup.+); .sup.1H-NMR (DMSO-d.sub.6, 200 MHz) .delta. 3.16
(m, 4H), 3.74 (m, 4H), 6.24 (s, 1H), 6.95 (d, J=8.6 Hz, 2H), 7.40
(d, J=2.6 Hz, 1H), 7.45 (dd, J=9.0, 2.6 Hz, 1H), 7.69 (d, J=9.0 Hz,
3H), 10.05 (s, 1H), 11.50 (br s, 1H); .sup.13C-NMR (DMSO-d.sub.6,
50 MHz) .delta. 176.38, 159.90, 149.38, 147.81, 135.04, 129.15,
125.76, 125.31, 122.78, 120.23, 116.18, 107.35, 105.34, 66.54,
49.37; Anal. Calcd for C.sub.19H.sub.18N.sub.2O.sub.3; C, 70.79; H,
5.63; N, 8.69.
[0269] 2-(4-Hydroxyphenyl)-6-pyrrolidinoquinolin-4-one (141) was
obtained from 120, using the same synthetic procedure as for 134.
The crude product was purified by column chromatography (silica
gel, CHCl.sub.3:MeOH=25:1) to give 141 as yellow solid. (0.1 g, 0.7
mmol). Yield: 64.9%; mp 304-306.degree. C.; MS (EI, 70 eV): m/z
306.3 (M.sup.+); IR (KBr): 1613.52 (C.dbd.O), 3132.53 (--NH),
3438.26 (--OH) cm.sup.-1; .sup.1H-NMR (DMSO-d.sub.o, 400 MHz)
.delta. 2.02 (m, 4H), 3.37 (m, 4H), 6.93 (s, 1H), 7.04 (d, J=8.4
Hz, 2H), 7.42 (dd, J=9.2, 2.0 Hz, 1H), 7.76 (d, J=8.4 Hz, 1H), 7.83
(d, J=8.4 Hz, 2H), 8.14 (d, J=9.2 Hz, 1H), 10.48 (s, 1H); Anal.
Calcd for C.sub.19H.sub.18N.sub.2O.sub.2; C, 74.49; H, 5.92; N,
9.14.
[0270] 2-(4-Hydroxyphenyl)-6-dimethylaminoquinolin-4-one (142) was
obtained from 121, using the same synthetic procedure as for 134.
The crude product was purified by column chromatography (silica
gel, CHCl.sub.3:MeOH=25:1) to give 142 as yellow solid. Yield:
74.2%; mp 321-323.degree. C.; MS (EI, 70 eV): m/z 280.1 (M.sup.+);
IR (KBr): 1617.38 (C.dbd.O), 3132.53 (--NH) cm.sup.-1; .sup.1H-NMR
(DMSO-d.sub.6, 200 MHz) .delta. 3.03 (s, 6H), 7.01 (d, J=8.6 Hz,
2H), 7.08 (d, J=2.8 Hz, 1H), 7.40 (d, J=6.0 Hz, 1H), 7.64 (dd,
J=9.4, 2.6 Hz, 1H), 7.84 (d, J=8.8 Hz, 2H), 8.22 (d, J=9.4 Hz, 1H),
11.30 (hr, 1H), 14.35 (br, 1H); Anal. Calcd for
C.sub.17H.sub.16N.sub.2O.sub.2; C, 72.84; H, 5.75; N, 9.99.
[0271] 2-(4-Hydroxy-3-methoxyphenyl)-6-morpholinoquinolin-4-one
(143) was obtained from 122, using the same synthetic procedure as
for 134. The crude product was purified by column chromatography
(silica gel, CHCl.sub.3:MeOH=25:1) to give 143 as yellow solid.
(0.15 g, 0.3 mmol). Yield: 63.0%; mp 297-299.degree. C.; MS (EI, 70
eV): m/z 352.1 (M.sup.+); .sup.1H-NMR (DMSO-d.sub.6, 200 MHz)
.delta. 3.15 (m, 4H), 3.77 (m, 4H), 3.88 (s, 3H), 6.28 (s, 1H),
6.92 (d, J=8.2 Hz, 1H), 7.27 (dd, J=8.2, 1.8 Hz, 1H), 7.33 (d,
J=1.8 Hz, 1H), 7.43 (d, J=2.6 Hz, 1H), 7.47 (dd, J=8.8, 2.6 Hz,
1H), 7.67 (d, J=8.8 Hz, 1H), 9.60 (s, 1H), 11.40 (s, 1H);
.sup.13C-NMR (DMSO-d.sub.6, 50 MHz) .delta. 176.85, 149.22, 148.29,
147.75, 137.15, 134.84, 125.98, 125.64, 122.71, 120.63, 120.00,
116.13, 111.65, 107.50, 105.68, 66.55, 56.31, 49.37; Anal. Calcd
for C.sub.20H.sub.20N.sub.2O.sub.4; C, 68.17; H, 5.72; N, 7.95.
[0272] 2-(4-Hydroxy-3-methoxyphenyl)-6-pyrrolidinoquinolin-4-one
(144) was obtained from 123, using the same synthetic procedure as
for 134. The crude product was purified by column chromatography
(silica gel, CHCl.sub.3:MeOH=25:1) to give 144 as yellow solid.
Yield: 63.7%; mp 310-312.degree. C.; MS (EI, 70 eV): m/z 336.2
(M.sup.+); IR (KBr): 1605.81 (C.dbd.O), 3163.39 (--NH) cm.sup.-1;
.sup.1H-NMR (DMSO-d.sub.6 200 MHz) .delta. 2.04 (m, 4H), 3.25 (m,
4H), 3.85 (s, 3H), 6.19 (s, 1H), 6.89 (d, J=8.2 Hz, 1H), 6.98 (d,
J=2.6 Hz, 1H), 7.03 (dd, J=8.2, 2.6 Hz, 1H), 7.22 (dd, J=8.8, 2.6
Hz, 1H), 7.30 (d, J=2.6 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 9.53 (s,
1H), 11.27 (s, 1H); Anal. Calcd for C.sub.20H.sub.20N.sub.2O.sub.3;
C, 71.41; H, 5.99; N, 8.33.
[0273] Dibenzyl
3-(4-oxo-6-(pyrrolidin-1-yl)-1,4-dihydroquinolin-2-yl)phenyl
phosphate (146). To a stirred solution of 138 (0.61 g, 2.0 mmol) in
dry THF (20 mL) was added NaH (500 mg, 12.5 mmol) at 0.+-.1.degree.
C. After the mixture was stirred for 1 h, tetrabenzyl pyrophosphate
(46) (2.15 g, 4.0 mmol) was added and stirring was continued for 30
min. The reaction mixture was filtered and washed with
CH.sub.2Cl.sub.2. The filtrate was concentrated under vacuum at a
temperature below 30.degree. C. to give crude product (145). Then,
the crude product in anhydrous MeOH (50 mL) was stirred at
25.degree. C. for 24 h. The precipitates were collected and
purified by column chromatography (SiO.sub.2, CH.sub.2Cl.sub.2:
EtOAc=3:7) to give 146 (0.37 g, 0.65 mmol). Yellow solid; yield:
32.7%; mp 169-171.degree. C.; MS (ESI): m/z 567.4 (M+H).sup.+;
.sup.1H-NMR (CDCl.sub.3, 200 MHz): .delta. 1.97 (m, 4H), 3.27 (m,
4H), 5.04 (s, 2H), 5.09 (s, 2H), 6.39 (s, 1H), 6.93 (dd, J=9.0, 2.6
Hz, 1H), 7.05 (d, J=7.8 Hz, 1H), 7.19-7.46 (m, 14H), 7.52 (d, J=8.8
Hz, 1H); Anal. (C.sub.33H.sub.31N.sub.2O.sub.5P)C, H, N.
[0274] 3-(4-Oxo-6-(pyrrolidin-1-yl)-1,4-dihydroquinolin-2-yl)phenyl
dihydrogen phosphate (147). A suspension of 146 (200 mg, 0.36 mmol)
in anhydrous MeOH (10 mL) was hydrogenated in the presence of 10%
Pd/C (100 mg) at 25.degree. C. for 20 min. The catalyst and
precipitate were collected and dissolved in 10% NaHCO.sub.3
solution and then filtered. The filtrate was acidified with dil aq
HCl and the precipitate was then collected and washed with acetone
to give 147 (97 mg, 0.25 mmol). Yellow solid; yield: 69.8%;
mp>300.degree. C.; MS (ESI): m/z 387.1 (M+H).sup.+; .sup.1H-NMR
(D.sub.2O+NaOD, 200 MHz): .delta. 1.78 (m, 4H), 3.08 (m, 4H), 6.70
(s, 1H), 7.12-7.20 (m, 3H), 7.28 (t, J=7.8 Hz, 1H), 7.40 (d, J=7.6
Hz, 1H), 7.49 (s, 1H), 7.61 (d, J=9.8 Hz, 1H); Anal.
(C.sub.19H.sub.19N.sub.2O.sub.5P) C, H, N.
II-2. Anticancer Activity
In Vitro Test
[0275] HL-60, Hep 3B, H460, MES-SA, MES-SAID x5 and Detroit 551
cells were treated with vehicle or test compounds for 48 h. The
cell growth rate was determined by MTT
(3-(4,5-dimethyl-thiazol-2-yl)-2,5-diphenyltetrazoliun bromide)
reduction assay. After 48 h incabution, the cell growth rate was
measured by scanning with an ELISA reader with a 570 nm filter and
the IC.sub.50 values of test compounds were calculated.
Results
[0276] The B-1 series of compounds has the following formula:
##STR00024##
[0277] Table 4 shows the B-1 series of compounds inhibited
proliferation of human cancer cells.
TABLE-US-00002 TABLE 4 IC.sub.50(.mu.M) MES- Ratio Of Detroit Cpd
R.sub.2' R.sub.3' R.sub.4' R.sub.5' HL-60 Hep 3B H460 MES-SA SA/Dx5
SA/Dx5 551 124 OCH.sub.2O H H 0.72 1.5 2.13 2.35 2.1 0.89 >2.5
126 OCH.sub.3 OCH.sub.3 H H 5.22 9.8 17.45 5.0 17.465 3.49 >50
128 OCH.sub.3 H H OCH.sub.3 1.2 3.11 3.47 2.03 8.205 4.04 16.6 130
OCH.sub.3 H H H 2.48 NA 7.36 2.5 9.708 3.88 >20 132 H H
OCH.sub.3 H >2.5 >2.5 >2.5 NA NA NA >2.5 134 OH H H H
2.1 8.78 8.3 2.38 10.419 4.38 >100 137 H OH H H 0.23 11.5 24.8
3.61 7.3 2.02 10 140 H H OH H 1.64 >10 >10 NA NA NA >l0
143 H OCH.sub.3 OH H 3.9 50 50 NA NA NA 50 143a OCH.sub.3 H H OH
93.8 >100 84.8 NA NA NA >100 143b OH H H OH 56.2 59.32
>100 NA NA NA >100 *: Cancer cell were treated with test
compound for 48 hrs.
[0278] The B-2 series of compounds has the following formula:
##STR00025##
[0279] Table 5 shows the B-2 series of compounds inhibited
proliferation of human cancer cells.
TABLE-US-00003 TABLE 5 IC.sub.50(.mu.M) MES- Ratio Of Detroit Cpd.
R.sub.2' R.sub.3' R.sub.4' R.sub.5' HL-60 Hep 3B H460 MES-SA SA/Dx5
SA/Dx5 551 125 OCH.sub.2O H H 0.08 0.2 0.2 0.1 0.183 1.83 >2.5
127 OCH.sub.3 OCH.sub.3 H H 0.53 1.2 1.78 0.802 1.71 2.13 >20
129 OCH.sub.3 H H OCH.sub.3 0.006 0.22 0.19 0.229 0.216 0.94 5.0
131 OCH.sub.3 H H H 0.13 0.3 0.57 0.445 0.451 1.01 >10 133 H H
OCH.sub.3 H >1.0 >1.0 >1.0 NA NA NA >1.0 135 OH H H H
0.36 1.31 0.86 0.846 1.0 1.18 25 138 H OH H H 0.009 0.28 0.4 0.734
0.32 0.23 1.39 141 H H OH H 0.04 1.1 1.56 NA NA NA >25 144 H
OCH.sub.3 OH H 0.038 0.38 0.56 NA NA NA >2.5 144a OCH.sub.3 H H
OH 1.62 7.38 6.5 3.69 25 6.78 9.1 144b OH H H OH NA NA NA NA NA NA
NA *: Cancer cell were treated with test compound for 48 hrs.
[0280] The B-3 series of compounds has the following formula:
##STR00026##
[0281] Table 6 shows the B-3 series of compounds inhibited
proliferation of human cancer cells.
TABLE-US-00004 TABLE 6 IC.sub.50(.mu.M) MES- Ratio Of Detroit Cpd.
R.sub.2' R.sub.3' R.sub.4' R.sub.5' HL-60 Hep 3B H460 MES-SA SA/Dx5
SA/Dx5 551 136 OH H H H 3.02 7.1 5.4 NA NA NA 100 139 H OH H H 0.06
1.0 6.2 0.931 0.852 0.92 10 142 H H OH H 0.64 9.0 0.56 NA NA NA 75
*: Cancer cell were treated with test compound for 48 hrs.
In Vivo Antitumor Activity Assay
[0282] The Hep-3B tumor cell line was purchased from American Type
Culture Collection (ATCC HB-8064, human ovarian carcinoma cells). A
culture medium of 90% DMEM, 10% Fetal Bovine Serum, supplemented
with 1% penicillin-streptomycin, was used. The tumor cells were
incubated in an atmosphere containing 5% CO.sub.2 at 37.degree.
C.
[0283] Balb/c Nude mice used in this study were male, 4-6 weeks
age, weighing 18-20 g and provided by National Animal Center. All
animals were housed in individually ventilated cages racks (IVC
Racks, 36 Mini Isolator system) under specific pathogen-free (SPF)
conditions throughout the experiment. Each cage (in cm, 26.7
length.times.20.7 width.times.14.0 height) was sterilized with
autoclave and contained eight mice. The animals were maintained in
a hygienic environment under controlled temperature (20-24.degree.
C.) and humidity (40%-70%) with a 12 hour light/dark cycle. The
animals were given free access to sterilized lab chow and
sterilized distilled water ad libitum. All aspects of this work,
i.e., housing, experimentation and disposal of animals, were
performed in general accordance with the Guide for the Care and Use
of Laboratory Animals (National Academy Press, Washington, D.C.,
1996).
[0284] In the xenograft tumor model of human ovarian carcinoma cell
lines (Hep-3B, ATCC HB-8064) in male Balb/c Nude mice, compound 147
prepared in 9% (w/v) NaHCO.sub.3 solution at doses of 7.5, 15 and
30 mg/kg (iv or po, qd) was administered five days per week for
four consecutive weeks and ceased at Day28. The tumor size and body
weight were monitored and recorded for 28 days. Human ovarian
carcinoma cells (HEP-3B, ATCC HB-8064) with 2.times.10.sup.6 cells
in 0.1 mL were injected subcutaneously into the right flank of the
mice. When the tumor growth reached >100 mm.sup.3 in volume
(assumed as day 0), the tumor-bearing animals were assigned into
several groups (six animals in each group) for study.
[0285] The body weight and tumor size were measured and recorded
every seven days during the experiment periods of 28 days. Tumor
volume (mm.sup.3) was estimated according to the formula of
length.times.(width).sup.2.times.0.5 in mm.sup.3. Tumor growth
inhibition was calculated as T/C (treatment/control) by the
following formula: T/C=(Tn-T.sub.0)/(Cn-C.sub.0).times.100% (To:
Tumor volume of treated group in Day 0; Tn: Tumor volume of treated
group in Day n; C.sub.0: Tumor volume of control group in Day 0;
Cn: Tumor volume of control group in Day n).
Results
[0286] The monophosphate (147) of 138 was evaluated in the Hep3B
xenograft nude mice model by oral route (po) at dosages of 7.5, 15
and 30 mg/kg/day. As shown by the results in FIG. 6 (A-C), compound
147 induced dose- and time-dependent inhibition of Hep3B tumor
growth. At the 7.5 mg/kg dose, the Hep3B inhibitory activity of 147
was found to exceed that of 10 mg/kg doxorubicin, and at the mg/kg
dose of 147, the weight of Hep3B tumor was reduced to 26.3% of that
of the control (FIG. 6B). During the course of antitumor
evaluation, no significant body weight changes were detected in
either the tested or the control group (FIG. 6C). Comparison of the
antitumor activity of 147 administered through two different routes
showed that the iv route yielded slightly greater activity than the
po route (FIG. 7A.about.7C).
III. C Series
Chemical Synthesis
[0287] The synthetic procedure of target compounds 153 is
illustrated in Scheme 11. The starting
2-amino-4,5-methylenedioxy-acetophenone (148) was first reacted
with naphthalene-1-carbonyl chloride (149) to give
N-(6-Acetyl-1,3-benzodioxol-5-yl)naphthalene-1-carboxamide (150).
Then, the intermediate (150) was subjected to cyclization in
dioxane, in the presence of NaOH, to afford
2-(1-Naphthalenyl)-6,7-methylenedioxyquinolin-4-one (151). Compound
151 was first reacted with tetrabenzylpyrophosphate in THF, in the
presence of NaH, to yield Dibenzyl
2-(1-naphthalenyl)-6,7-methylenedioxyquinolin-4-yl Phosphate (152).
Compound 152 was then subjected to catalytic hydrogenation in MeOH
to give its diphosphoric acid (153).
[0288] The synthetic procedure of target compounds 158 is
illustrated in Scheme 12. The starting 2-amino-4,5-methylenedioxy
acetophenone (148) was first reacted with benzo[b]furan-3-carbonyl
chloride (154) to give
N-(6-Acetyl-1,3-benzodioxol-5-yl)-1-benzofuran-3-carboxamide (155).
Then, the intermediates (155) was subjected to cyclization in
dioxane, in the presence of NaOH, to afford
2-(3-Benzo[b]furyl)-6,7-methylenedioxyquinolin-4-one (156).
Compound 156 was first reacted with tetrabenzylpyrophosphate in
THF, in the presence of NaH, to yield dibenzyl
2-(3-benzo[b]furyl)-6,7-methylenedioxyquinolin-4-yl phosphate
(157). Compound 157 was then subjected to catalytic hydrogenation
in MeOH to give its diphosphoric acid (158).
##STR00027##
##STR00028##
Examples
[0289] General Experimental Procedures. All of the reagents and
solvents were obtained commercially and used without further
purification. Reactions were monitored by thin-layer
chromatography, using Merck plates with fluorescent indicator (TLC
Silica gel 60 F.sub.254). The following adsorbent was used for
column chromatography: silica gel 60 (Merck, particle size
0.063-0.200 mm). Melting points were determined on a Yanaco MP-500D
melting point apparatus and were uncorrected. IR spectra were
recorded on Shimadzu IRPrestige-21 spectrophotometers as KBr
pellets. NMR spectra were obtained on a Bruker Avance DPX-200
FT-NMR spectrometer in CDCl.sub.3 or DMSO. The following
abbreviations are used: s, singlet; d, doublet; t, triplet; q,
quartet; dd, double doublet and m, multiplet. EI-MS spectra were
measured with an HP 5995 GC-MS instrument. ESI-MS spectra were
measured with a Finnigan LCQ ion-trap mass spectrometer (TSQ
Quantum, Thermo Finnigan Corporation, San Jose, Calif.). Elemental
analyses (C, H, and N) were performed on a Perkin-Elmer 2400 Series
II CHNS/O analyzer, and the results were within .+-.0.4% of the
calculated values.
[0290] N-(6-Acetyl-1,3-benzodioxol-5-yl)naphthalene-1-carboxamide
(150). Into solutions of 149 (5.0 mmol) in 200 mL of dry toluene
were added triethylamine (4 mL) and 2-amino-4,5-methylenedioxy
acetophenone (148) (5 mmol). The mixtures were stirred at
20.+-.2.degree. C. for 24 h and then evaporated. The residues were
washed with acetone and EtOH and then recrystallized from acetone
or EtOH to form 150. Obtained as a grayish-white solid; mp
143-144.degree. C.; ESI-MS (Positive mode): m/z 334 [M+H].sup.+;
.sup.1H-NMR (400 MHz, DMSO-d.sub.6, .delta.): 2.59 (3H, s), 6.20
(2H, s), 7.60-7.68 (4H, m), 7.87 (1H, d, J=7.2 Hz), 8.05-8.07 (1H,
m), 8.15 (1H, d, J=8.0 Hz), 8.33-8.38 (2H, m), 12.52 (1H, s); IR
(KBr): 1647, 1672 (C.dbd.O) cm.sup.-1.
[0291] 2-(1-Naphthalenyl)-6,7-methylenedioxyquinolin-4-one (151).
Into a suspension of 150 (2.95 mmol) in t-butyl alcohol (100 mL)
was added potassium t-butoxide (1.66 g, 14.7 mmol). The mixture was
refluxed under argon for 12 h, cooled, and poured into a 10%
ammonium chloride solution (100 mL). The solid precipitate was
collected and washed with EtOH. The crude product was purified by
flash chromatography (silica gel, CH.sub.2Cl.sub.2:EtOH 16:1-10:1).
Yield 52% from 150 as a grayish-white solid; mp>350.degree. C.;
ESI-MS (Positive mode): m/z 316 [M+H].sup.+; .sup.1H-NMR
(DMSO-d.sub.6, 8): 6.08 (1H, s), 6.15 (2H, s), 7.03 (1H, s), 7.46
(1H, s), 7.56-7.63 (2H, m), 7.63-7.70 (2H, m), 7.83 (1H, d, J=7.6
Hz), 8.06 (1H, d, J=7.6 Hz), 8.11 (1H, d, J=7.6 Hz), 11.90 (1H, s).
IR (KBr): 1653 (C.dbd.O) cm.sup.-1; Anal. Calcd for
C.sub.20H.sub.13NO.sub.3: C, 76.18; H, 4.16; N, 4.44. Found: C,
75.60; H, 3.94; N, 4.29.
[0292] Dibenzyl 2-(1-naphthalenyl)-6,7-methylenedioxyquinolin-4-yl
Phosphate (152). A suspension of 151 (1.20 g, 3.81 mmol) in
anhydrous MeOH (10 mL) was stirred at 25.degree. C. for 24 h. The
precipitates were collected and purified by silica gel column
chromatography eluted by n-hexane and EtOAc to give 152. Orange
oil; yield: 63.7%; ESI-MS (Positive mode): nil: 576 [M+H].sup.+;
.sup.1H-NMR (CDCl.sub.3. 500 MHz): .delta. 5.21 (4H, dd, J=8.30,
8.15 Hz), 6.17 (2H, s), 7.23 (1H, s), 7.28-7.37 (9H, m), 7.40-7.60
(7H, m), 7.95 (2H, m), 8.09 (1H, d, J=8.20 Hz).
[0293] 2-(1-Naphthalenyl)-6,7-methylenedioxyquinolin-4-yl
Dihydrogen Phosphate (153). A suspension of 152 (894.8 mg, 1.55
mmol) in anhydrous MeOH (40 mL) was hydrogenated in the presence of
10% Pd/C (456.7 mg) at 25.degree. C. for 15 min. The catalyst and
precipitate were collected and dissolved in 10% NaHCO.sub.3
solution and then filtered. The filtrate was acidified with dil aq
HCl and the precipitate was then collected and washed with acetone
to give 153. Yellow solid; yield: 94.1%; ESI-MS (Negative mode):
m/z 394 [M-H].sup.-; .sup.1H-NMR (D.sub.2O+NaOD, 500 MHz): .delta.
6.13 (2H, s), 7.26 (1H, s), 7.50 (1H, ddd, J=8.23, 7.33, 1.20 Hz),
7.55-7.58 (2H, m), 7.62-7.70 (3H, m), 7.98 (1H, d, J=8.53 Hz), 8.02
(1H, d, J=8.96 Hz); .sup.13C-NMR (D.sub.2O+NaOD, 125 MHz): .delta.
98.65, 102.15, 103.54, 109.80, 110.00, 118.35, 125.66, 126.37,
126.84, 127.40, 128.34, 128.97, 130.89, 133.50, 138.15, 146.58,
147.34, 151.27, 158.15, 158.23.
[0294] N-(6-Acetyl-1,3-benzodioxol-5-yl)-1-benzofuran-3-carboxamide
(155). Into solutions of 154 (5.0 mmol) in 200 mL of dry toluene
were added triethylamine (4 mL) and 2-amino-4,5-methylenedioxy
acetophenone (148) (5 mmol). The mixtures were stirred at
20.+-.2.degree. C. for 24 h and then evaporated. The residues were
washed with acetone and EtOH and then recrystallized from acetone
or EtOH to form 155. Obtained as a pale-yellow solid; mp
144-145.degree. C.; ESI-MS (Positive mode): m/z 324 [M+H].sup.+;
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 2.63 (3H, s), 6.19
(2H, s), 7.41-7.50 (21-1, m), 7.68 (1H, s), 7.75 (1H, dd, J=1.6,
6.8 Hz), 8.15 (1H, dd, J=2.0, 8.8 Hz), 8.27 (1H, s), 8.71 (1H, s),
12.63 (1H, s); IR (KBr): 1635, 1677 (C.dbd.O) cm.sup.-1.
[0295] 2-(3-Benzo[b]furyl)-6,7-methylenedioxyquinolin-4-one (156).
Into a suspension of 155 (2.95 mmol) in t-butyl alcohol (100 mL)
was added potassium t-butoxide (1.66 g, 14.7 mmol). The mixture was
refluxed under argon for 12 h, cooled, and poured into a 10%
ammonium chloride solution (100 mL). The solid precipitate was
collected and washed with EtOH. The crude product was purified by
flash chromatography (silica gel, CH.sub.2Cl.sub.2: EtOH
16:1-10:1). Obtained as a pale-yellow solid from 155; yield 17%;
mp>315.degree. C.; ESI-MS (Positive mode): m/z 306 [M+H].sup.+;
.sup.1H-NMR (400 MHz, DMSO-d.sub.6): .delta. 6.12 (2H, s), 6.49
(1H, s), 7.13 (1H, s), 7.36-7.45 (3H, m), 7.69 (1H, d, J=8.0 Hz),
8.14 (1H, s), 8.52 (1H, s); IR (KBr): 1626 (C.dbd.O) cm.sup.-1;
Anal. Calcd for C.sub.18H.sub.11NO.sub.4: C, 70.82; H, 3.63; N,
4.59. Found: C, 70.52; H, 3.95; N, 4.21.
[0296] Dibenzyl 2-(3-benzo[b]furyl)-6,7-methylenedioxyquinolin-4-yl
Phosphate (157). To a stirred solution of 151 (0.04 g, 0.13 mmol)
in dry tetrahydrofuran (40 mL) was added NaH 60% in mineral oil
(48.0 mg, 2.0 mmol) at 0.+-.1.degree. C. After the mixture was
stirred for 1 h, tetrabenzyl pyrophosphate (139.8 mg, 0.26 mmol)
was added and stirring was continued for 60 min. The reaction
mixture was filtered and washed with tetrahydrofuran. The filtrate
was concentrated under vacuum at a temperature below 30.degree. C.
The residue was purified by column chromatography (SiO.sub.2,
n-hexane/EtOAc) to give 157. Obtained as a white solid from 156;
yield: 86.8%; ESI-MS (Positive mode): m/z 566 [M+H].sup.+;
.sup.1H-NMR (500 MHz. CDCl.sub.3): .delta. 5.24 (4H, dd, J=9.5, 9.5
Hz), 6.15 (2H, s), 7.16 (1H, s), 7.34-7.42 (12H, m), 7.45 (1H, s),
7.58 (1H, d, J=9.5 Hz), 7.59 (1H, s), 8.02 (1H, s), 8.47 (1H, d,
J=7.5 Hz); .sup.13C-NMR (D2O+NaOD, 125 MHz): .delta. 70.67, 70.63,
97.30, 100.00, 101.87, 105.93, 106.72, 111.48, 116.94, 121.76,
122.62, 123.51, 124.82, 125.66, 128.20, 128.72, 128.96, 134.98,
144.59, 147.92, 148.43, 150.97, 151.43, 153.47, 156.06.
[0297] 2-(3-Benzo[b]furyl)-6,7-methylenedioxyquinolin-4-yl
Dihydrogen Phosphate (158). A suspension of 157 (80.1 mg, 0.14
mmol) in anhydrous MeOH (40 mL) was hydrogenated in the presence of
10% Pd/C (40.0 mg) at 25.degree. C. for 15 min. The catalyst and
precipitate were collected and dissolved in 10% NaHCO.sub.3
solution and then filtered. The filtrate was acidified with dil aq
HCl and the precipitate was then collected and washed with acetone
to give 158. Obtained as white solid; yield: 46.3%; ESI-MS
(Positive mode): m/z 386 [M+H].sup.+, 408 [M+Na].sup.+; ESI-MS
(Negative mode): m/z 384 [M-H].sup.-; .sup.1H-NMR (D.sub.2O+NaOD,
500 MHz): .delta. 6.12 (2H, s), 7.32 (1H, s), 7.42 (2H, m), 7.56
(1H, s), 7.63 (1H, d, J=8.0 Hz), 7.78 (1H, s), 8.29 (1H, d, J=7.0
Hz), 8.40 (1H, s).
III-2. Anticancer Activity
In Vitro Test
[0298] MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide) assays. HL-60, HCT-116, A549, Hep 3B, KB, Kb-VIN and DU145
cells were treated with tested compounds for the indicated periods.
After treatment, cells were washed once with PBS and incubated with
MTT (Sigma, St. Louis, Mo., USA) for 2 h. The formazan precipitate
was dissolved in 150 .mu.L of DMSO, and the absorbance was measured
with an ELISA reader at 570 nm.
Results
TABLE-US-00005 [0299] TABLE 7 IC.sub.50 (.mu.M) Values from In
Vitro Cytotoxicity Testing of 151 and 156. 151 (JMC-39)
##STR00029## 156 (JMC-37) ##STR00030## Compound HL-60 HCT-116 A549
Hep 3B KB Kb-VIN DU145 151 0.07 0.07 0.13 0.07 0.13 0.19 0.13 156
0.03 0.05 2.98 0.09 1.05 0.59 1.87 * Not assayed
##STR00031## ##STR00032##
IV. D Series
Chemical Synthesis
[0300] The compound 159 was derived into a phosphate (169)
following the synthetic method in Scheme 13. As illustrated,
3-(Benzyloxy)-5-methoxybenzoyl chloride (163) obtained from 159
with steps a-d was reacted with 2-amino-4,5-methylenedioxy
acetophenone (148) in THF/triethylamine, to give
N-(6-acetylbenzo[d][1,3]dioxol-5-yl)-3-(benzyloxy)-5-methoxybenzamide
(164). Compound 164 was further refluxed in NaOH/1,4-dioxane to
yield 165. Subsequently, by following the steps g-j, target
compound 169 was afforded as white solid.
Examples
[0301] General Experimental Procedures. All of the reagents and
solvents were obtained commercially and used without further
purification. Reactions were monitored by thin-layer
chromatography, using Merck plates with fluorescent indicator (TLC
Silica gel 60 F.sub.254). The following adsorbent was used for
column chromatography: silica gel 60 (Merck, particle size
0.063-0.200 mm). Melting points were determined on a Yanaco MP-500D
melting point apparatus and were uncorrected. IR spectra were
recorded on Shimadzu IRPrestige-21 spectrophotometers as KBr
pellets. NMR spectra were obtained on a Bruker Avance DPX-200
FT-NMR spectrometer in CDCl.sub.3 or DMSO. The following
abbreviations are used: s, singlet; d, doublet; t, triplet; q,
quartet; dd, double doublet and m, multiplet. EI-MS spectra were
measured with an HP 5995 GC-MS instrument. ESI-MS spectra were
measured with a Finnigan LCQ ion-trap mass spectrometer (TSQ
Quantum, Thermo Finnigan Corporation, San Jose, Calif.). Elemental
analyses (C, H, and N) were performed on a Perkin-Elmer 2400 Series
II CHNS/O analyzer, and the results were within .+-.0.4% of the
calculated values.
Methyl 3-(benzyloxy)-5-hydroxybenzoate (160)
[0302] A mixture of 8.40 g (0.05 mmol) methyl 3,5-dihydroxybenzoate
(159) and 7.60 g (0.055 mmol) of potassium carbonate in 250 mL of
acetone was stirred at room temperature for 30 min. Then 8.55 g
(0.05 mmol) of benzyl bromide dissolved in 100 mL of acetone was
added. The suspension was refluxed for 24 h. The solid was
filtered, and the filtrate was evaporated. The residue was purified
by column chromatography (SiO.sub.2, CH.sub.2Cl.sub.2/EtOAc=9/1) to
give 160.
[0303] Obtained as a white solid from methyl 3,5-dihydroxybenzoate
(159); yield 34%; .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.3.92
(3H, s), 5.05 (2H, s), 6.77 (1H, dd, J=2.35, 2.20 Hz), 7.13 (1H,
s), 7.27-7.28 (2H, m), 7.34-7.45 (5H, m); .sup.13C-NMR (50 MHz,
CDCl.sub.3): .delta. 52.34, 70.27, 107.44, 108.08, 109.48, 127.53
(2C), 128.11, 128.60 (2C), 131.99, 136.41, 137.45, 156.80,
160.00.
Methyl 3-(benzyloxy)-5-methoxybenzoate (161)
[0304] A suspension of 4.0 g (0.0165 mmol) methyl
3-(benzyloxy)-5-hydroxybenzoate (160), 6.84 g (0.0495 mmol)
potassium carbonate, and 11.71 g (0.0825 mmol) iodomethane in the
200 mL of acetone was stirred at room temperature for 24 h. After
the mixture was filtered and evaporated, the residue was washed
with water. The methyl 3-(benzyloxy)-5-methoxybenzoate (161) was
obtained as a white solid.
[0305] Obtained as a white solid from methyl
3-(benzyloxy)-5-hydroxybenzoate (160); yield 85%; .sup.1H NMR (200
MHz, CDCl.sub.3): .delta.3.83 (3H, s), 3.92 (3H, s), 5.09 (2H, s),
6.74 (1H, t, J=2.45 Hz), 7.21 (1H, dd, J=2.45, 1.22 Hz), 7.29 (1H,
dd, J=2.45, 1.22 Hz), 7.34-7.48 (5H, m); .sup.13C-NMR (50 MHz,
CDCl.sub.3): .delta. 52.22, 55.55, 70.24, 106.53, 107.47, 107.98,
127.54, 128.09, 128.59, 131.99, 136.44, 159.75, 160.61.
3-(Benzyloxy)-5-methoxybenzoic acid (162)
[0306] 4.45 g (0.0174 mmol) of methyl
3-(benzyloxy)-5-methoxybenzoate (161) was suspended in 120 mL of
95% ethanol and 5 mL water. An amount of 2.00 g (0.05 mmol) of
sodium hydroxide was added. The mixture was heated at reflux for 1
h. After the mixture was evaporated, the residue was quenched with
150 mL of water. The solution was neutralized with dil aq HCl and
then the precipitate was collected and washed with water and
acetone to give 162.
[0307] Obtained as a white solid from methyl
3-(benzyloxy)-5-methoxybenzoate (161); yield 90%; .sup.1H NMR
(DMSO-d.sub.6, 200 MHz): .delta. 3.81 (3H, s), 5.09 (2H, s), 6.74
(1H, t, J=2.45 Hz), 7.25 (1H, dd, J=2.45, 1.35 Hz), 7.20-7.46 (6H,
m); .sup.13C-NMR (DMSO-d.sub.6, 50 MHz): .delta. 55.89, 69.94,
106.19, 107.57, 108.17, 128.12, 128.33, 128.90, 133.34, 137.22,
138.78, 159.88, 160.80, 167.36, 176.99.
3-(Benzyloxy)-5-methoxybenzoyl chloride (163)
[0308] 3-(Benzyloxy)-5-methoxybenzoic acid (162) (2.57 g, 0.01
mmol) and thionyl chloride (4.80 g, 0.04 mmol) were suspended in
200 mL of dry toluene. The reaction mixture was stirred for 30 min
and then dimethyl formamide (3 drops) was added. The mixture was
stirred for 24 h and then evaporated to dryness. The residue was
directly used for the next step without further purification.
N-(6-acetylbenzo[d][1,3]-dioxol-5-yl)-3-(benzyloxy)-5-methoxybenzamide
(164)
[0309] Into solutions of 163 (2.77 g, 0.01 mmol) in 200 mL of dry
tetrahydrofuran were added triethylamine (10 mL) and
2-amino-4,5-methylenedioxy acetophenone (148) (1.79 g, 0.01 mmol).
The mixtures were stirred at room temperature for 24 h and then
evaporated. The residue was purified by column chromatography
(SiO.sub.2, CH.sub.2Cl.sub.2/EtOAc=3/1) to give 164.
[0310] Obtained as a grayish white solid from
3-(benzyloxy)-5-methoxybenzoyl chloride (163) and
2-amino-4,5-methylenedioxy acetophenone (148); yield 75%; ESI-MS
(Positive mode): m/z 442 [M+Na].sup.+; .sup.1H NMR (DMSO-d.sub.6,
500 MHz): .delta.2.64 (3H, s), 3.84 (3H, s), 5.20 (2H, s), 6.19
(2H, s), 6.87 (1H,$), 7.09 (1H, s), 7.16 (1H, s), 7.37 (1H, d,
J=7.43 Hz), 7.43 (1H, t, J=7.43 Hz), 7.49 (1H, d, 7.43 Hz), 7.68
(1H, s), 8.34 (1H, s), 13.06 (1H, s); .sup.13C-NMR (DMSO-d.sub.6,
125 MHz): .delta. 29.32, 55.99, 70.12, 98.96, 100.77, 102.91,
105.03, 105.67, 106.45, 111.25, 116.53, 128.28, 128.30, 128.95,
136.90, 137.05, 138.27, 143.11, 152.68, 160.28, 161.20, 164.99,
200.00.
2-(3-Benzyloxy-5-methoxyphenyl)-6,7-methylenedioxyquinolin-4-one
(165)
[0311] Into a suspension of 164 (3.33 g, 0.0079 mmol) in 200 mL of
1,4-dioxane was added sodium hydroxide (2.50 g, 0.0635 mmol). The
mixture was refluxed for 24 h. After the reaction mixture was
evaporated, 100 mL of 10% ammonium chloride solution was added. The
mixture was stirred for 12 h, and then the precipitate was
collected and washed with water and acetone.
[0312] Obtained as a grayish white solid; yield 75%; mp
235-238.degree. C.; ESI-MS (Positive mode): m/z 402 [M+H].sup.+;
ESI-MS (Negative mode): m/z 400 [M-H].sup.-; .sup.1H NMR
(DMSO-d.sub.6, 500 MHz): .delta. 3.85 (3H, s), 5.22 (2H, s), 6.16
(2H, s), 6.31 (1H, s, br), 6.79 (1H, s), 6.95 (1H, s), 7.04 (1H,
s), 7.21 (1H, s), 7.36-7.50 (6H, m), 11.50 (1H, s, br);
.sup.13C-NMR (DMSO-d.sub.6, 125 MHz): .delta. 56.04, 70.10, 97.72,
101.76, 102.40, 103.14, 105.95, 106.60, 107.15, 110.00, 120.46,
128.25, 128.42, 128.96, 137.27, 137.82, 145.66, 151.57, 160.31,
161.23, 175.40.
2-(3-Hydroxy-5-methoxyphenyl)-6,7-methylenedioxyquinolin-4-one
(166)
[0313] A suspension of 0.5 g (1.245 mmol) of 165 and 0.25 g of
palladium (10 wt % on activated carbon) in 60 mL of methanol was
stirred at room temperature under hydrogen gas atmosphere for 24 h.
The precipitate were collected and dissolved in 10% NaOH solution
and then filtered. The filtrate was acidified with dil aq HCl and
the precipitate was then collected and washed with acetone and
water to give 166.
[0314] Obtained as white solid; yield: 77%; mp>300.degree. C.;
ESI-MS (Positive mode): m/z 312 [M+H].sup.+, 408 [M+Na].sup.+;
ESI-MS (Negative mode): m/z 310 [M-H].sup.-; .sup.1H NMR
(DMSO-d.sub.6, 500 MHz): .delta. 3.80 (3H, s), 6.16 (2H, s), 6.24
(1H, s, br), 6.52 (1H, s), 6.77 (1H, s), 6.78 (1H, s), 7.22 (1H,
s), 7.40 (1H, s), 9.91 (1H, s), 11.56 (1H, s, br); .sup.13C-NMR
(DMSO-d.sub.6, 125 MHz): .delta. 55.77, 97.83, 101.52, 102.39,
103.29, 104.31, 106.74, 107.17, 120.79, 136.78, 137.77, 145.69,
149.27, 151.57, 159.38, 161.24, 175.93.
Dibenzyl
2-(3-([bis-[(benzyl)oxy]]phosphoryl)oxy-5-methoxyphenyl)-6,7-meth-
ylenedioxyquinolin-4-yl phosphate (167)
[0315] A suspension of 203.9 mg (0.65 mmol) of 166, 131.0 mg of NaH
60% in mineral oil and 705.4 mg (1.31 mmol) of tetrabenzyl
pyrophosphate in 20 mL of dry tetrahydrofuran. The mixture was
stirred at room temperature for 10 min. The reaction mixture was
filtered and washed with tetrahydrofuran. The filtrate was
concentrated under vacuum at a temperature below 30.degree. C.
[0316] Obtained as a yellow oil; yield: 85%; ESI-MS (Positive
mode): m/z 832 [M+H].sup.+; .sup.1H-NMR (CDCl.sub.3, 200 MHz):
.delta. 3.77 (3H, s), 5.12 (4H, d, J=8.31 Hz), 5.17 (4H, d, J=9.54
Hz), 6.09 (2H, s), 6.78 (1H, m), 7.10 (1H, s), 7.23 (1H, s),
7.27-7.40 (22H, m), 7.52 (1H, d, J=0.98 Hz); .sup.13C-NMR
(CDCl.sub.3, 50 MHz): .delta. 55.64, 70.01, 70.12, 70.53, 70.65,
97.16, 101.90, 106.07, 106.62, 110.04, 111.41, 111.52, 117.39,
117.53, 128.09, 128.14, 128.59, 128.67, 128.90, 134.91, 135.02,
135.38, 135.52, 141.49, 151.49, 151.64, 151.78, 153.74, 153.87,
154.86, 160.82.
2-(3-([bis-[(benzyl)oxy]]phosphoryl)oxy-5-methoxyphenyl)-6,7-methylenediox-
yquinolin-4-one (168)
[0317] A suspension of 0.92 g (1.11 mmol) of 167 in 100 mL of
methanol was stirred at 25.degree. C. for 48 h. The precipitates
were collected and purified by column chromatography (SiO.sub.2,
EtOAc) to give 168.
[0318] Obtained as a white solid; yield: 45%; ESI-MS (Positive
mode): m/z 572 [M+H].sup.+, 594[M+Na].sup.+; ESI-MS (Negative
mode): m/z 570 [M-H].sup.-; .sup.1H-NMR (CDCl.sub.3, 500 MHz):
.delta. 3.64 (3H, s), 5.07 (4H, d, J=9.20 Hz), 5.99 (2H, s), 6.37
(1H, s), 6.79 (1H, s), 7.09 (1H, s), 7.18 (1H, s), 7.27-7.29 (22H,
m), 7.59 (1H, s); .sup.13C-NMR (CDCl.sub.3, 125 MHz): .delta.
55.57, 70.39, 70.43, 97.35, 101.83, 102.25, 107.57, 107.76, 107.82,
109.93, 110.00, 110.80, 110.90, 121.03, 128.09, 128.66, 128.87,
134.98, 134.02, 145.92, 148.07, 151.35, 151.40, 151.91, 160.90,
177.41.
2-(3-(dihydrogen)phosphate-5-methoxyphenyl)-6,7-methylenedioxyquinolin-4-o-
ne (169)
[0319] A suspension of 38.9 mg (0.068 mmol) of 168 and 20 mg of
palladium (10 wt % on activated carbon) in 20 mL of anhydrous
methanol was stirred at room temperature under hydrogen gas
atmosphere for 15 min. The precipitate were collected and dissolved
in 10% NaHCO.sub.3 solution and then filtered. The filtrate was
acidified with dil aq HCl and the precipitate was then collected
and washed with acetone to give 169.
[0320] Obtained as white solid; yield: 80%; ESI-MS (Negative mode):
m/z 390 [M-H].sup.+; .sup.1H NMR (D.sub.2O+NaOD, 500 MHz): .delta.
3.88 (3H, s), 6.01 (2H, s), 6.78 (1H, s), 6.93 (1H, s), 7.14 (1H,
s), 7.15 (1H, s), 7.25 (1H, s), 7.44 (1H, s); .sup.13C-NMR
(D.sub.2O+NaOD, 125 MHz): .delta. 55.74, 99.41, 101.53, 103.57,
105.41, 106.64, 107.14, 112.32, 120.87, 142.31, 145.41, 147.13,
150.33, 155.24, 157.79, 159.78, 172.61.
IV-2. Anticancer Activity
In Vitro Tests
[0321] MTT (3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide) assays. HL-60, Hep 3B, H460, A498, Colo205 and Detroit 551
cells were treated with tested compounds for the indicated periods.
After treatment, cells were washed once with PBS and incubated with
MTT (Sigma, St. Louis, Mo., USA) for 2 h. The formazan precipitate
was dissolved in 150 .mu.L of DMSO, and the absorbance was measured
with an ELISA reader at 570 nm.
Results
[0322] Table 8 shows IC.sub.50 (.mu.M) Values from In Vitro
Cytotoxicity Testing of 166.
TABLE-US-00006 TABLE 8 166 ##STR00033## Compound HL-60 Hep 3B H460
A498 Colo205 Detroit 551 166 0.4 >50 >50 >50 >50
>50
[0323] Representative compounds of the present invention are Show
in Table 9 below.
TABLE-US-00007 TABLE 9 (Formula I) ##STR00034## Substituent on
Comp'd Structure Name Formula I 16 ##STR00035## 2-(2-Fluorophenyl)-
5,6-dimethoxyquinolin- 4-one R = H W = 2-fluorophenyl R5 = methoxy
R6 = methoxy R7 = hydrogen 17 ##STR00036## 2-(3-Fluorophenyl)-
5,6-dimethoxyquinolin- 4-one R = H W = 3-fluorophenyl R5 = methoxy
R6 = methoxy R7 = hydrogen 18 ##STR00037## 2-(4-Fluorophenyl)-
5,6-dimethoxyquinolin- 4-one R = H W = 4-fluorophenyl R5 = methoxy
R6 = methoxy R7 = hydrogen 19 ##STR00038## 2-(2-Fluorophenyl)-
5,6-methylenedioxy quinolin-4-one R = H W = 2-fluorophenyl R5, R6 =
methylenedioxy R7 = hydrogen 20 ##STR00039## 2-(3-Fluorophenyl)-
5,6-methylenedioxy quinolin-4-one R = H W = 3-fluorophenyl R5, R6 =
methylenedioxy R7 = hydrogen 21 ##STR00040## 2-(4-Fluorophenyl)-
5,6-methylenedioxy quinolin-4-one R = H W = 4-Fluorophenyl R5, R6 =
methylenedioxy R7 = hydrogen 22 ##STR00041## 7-Benzyloxy-2-(2-
fluorophenyl)-6- methoxyquinolin- 4-one R = H W = 2-fluorophenyl R5
= hydroxyl R6 = methoxy R7 = O-benzyl R7 = hydrogen 23 ##STR00042##
7-Benzyloxy-2-(3- fluorophenyl)-6- methoxyquinolin-4- one R = H W =
3-fluorophenyl R5 = hydroxyl R6 = methoxy R7 = O-benzyl 24
##STR00043## 7-Benzyloxy-2-(4- fluorophenyl)-6- methoxyquinolin-
4-one R = H W = 4-fluorophenyl R5 = hydroxyl R6 = methoxy R7 =
O-benzyl 37 ##STR00044## 2-(2-Fluorophenyl)- 5-hydroxy-6-
methoxyquinolin- 4-one R = H W = 2-fluorophenyl R5 = hydroxyl R6 =
methoxy R7 = hydrogen 38 ##STR00045## 2-(3-Fluorophenyl)-
5-hydroxy-6- methoxyquinolin- 4-one R = H W = 3-fluorophenyl R5 =
hydroxyl R6 = methoxy R7 = hydrogen 39 ##STR00046##
2-(4-Fluorophenyl)- 5-hydroxy-6- methoxyquinolin- 4-one R = H W =
4-fluorophenyl R5 = hydroxyl R6 = methoxy R7 = hydrogen 40
##STR00047## 2-(2-Fluorophenyl)- 5,6-dihydroxyquinolin- 4-one R = H
W = 2-fluorophenyl R5 = hydroxyl R6 = hydroxyl R7 = hydrogen 41
##STR00048## 2-(3-Fluorophenyl)- 5,6-dihydroxyquinolin- 4-one R = H
W = 3-fluorophenyl R5 = hydroxyl R6 = hydroxyl R7 = hydrogen 42
##STR00049## 2-(4-Fluorophenyl)- 5,6-dihydroxyquinolin- 4-one R = H
W = 4-fluorophenyl R5 = hydroxyl R6 = hydroxyl R7 = hydrogen 43
##STR00050## 2-(2-Fluorophenyl)- 7-hydroxy-6-methoxy-
quinolin-4-one R = H W = 2-fluorophenyl R5 = hydroxyl R6 = methoxy
R7 = hydroxyl 44 ##STR00051## 2-(3-Fluorophenyl)-
7-hydroxy-6-methoxy- quinolin-4-one R = H W = 3-fluorophenyl R5 =
hydroxyl R6 = methoxy R7 = hydroxyl 45 ##STR00052##
2-(4-Fluorophenyl)- 7-hydroxy-6-methoxy- quinolin-4-one R = H W =
4-fluorophenyl R5 = hydroxyl R6 = methoxy R7 = hydroxyl 48
##STR00053## 2-(3-Fluorophenyl)- 6-methoxyquinoline- 4,5-diyl
bis(dibenzyl phosphate) R = PO(O-benzyl)2 W = 3-fluorophenyl R5 =
OR8 R6 = methoxy R7 = hydrogen R8 = P(.dbd.O)(O-benzyl)2 49
##STR00054## 2-(3-Fluorophenyl)- 6-methoxyquinoline- 4,5-diyl
bis(dihydrogen phosphate) R = PO(OH)2 W = 3-fluorophenyl R5 = OR8
R6 = methoxy R7 = hydrogen R8 = --P(.dbd.O)(OH).sub.2 50
##STR00055## 2-(3-Fluorophenyl)- 6-methoxyquinoline- 4,5-diyl
bis(disodium phosphate) R = PO(ONa)2 W = 3-fluorophenyl R5 = OR8 R6
= methoxy R7 = hydrogen R8 = P(.dbd.O)(ONa)2 51 ##STR00056##
Dibenzyl 2-(3-fluorophenyl)-6- methoxy-4-oxo-1,4-
dihydroquinolin-5-yl phosphate R = H W = 3-fluorophenyl R5 = OR8 R6
= methoxy R7 = hydrogen R8 = P(.dbd.O)(O-benzyl)2 52 ##STR00057##
2-(3-Fluorophenyl)- 6-methoxy-4-oxo-1,4- dihydroquinolin-5-yl
dihydrogen phosphate R = H W = 3-fluorophenyl R5 = OR8 R6 = methoxy
R7 = hydrogen R8 = P(.dbd.O)(OH)2 53 ##STR00058## Sodium
2-(3-fluorophenyl)-6- methoxy-4-oxo-1,4- dihydroquinolin-5-yl
phosphate R = H W = 3-fluorophenyl R5 = OR8 R6 = methoxy R7 =
hydrogen R8 = P(.dbd.O)(ONa)2 124 ##STR00059## 2-(benzo[d][1,3]
dioxol-86-yl)-6- morpholinoquinolin- 4-one R = H W = benzo[d]
[1,3]dioxol-4-yl, R5 = hydrogen R6 = N-morpholino R7 = hydrogen 125
##STR00060## 2-(benzo[d][1,3] dioxol-4-yl)-6-pyrrol-
idinoquinolin-4-one R = H W= benzo[d] [1,3]dioxol-4-yl, R5 =
hydrogen R6 = N-pyrrolindino R7 = hydrogen 126 ##STR00061##
2-(2,3-dimethoxy- phenyl)-6-morpholino- quinolin-4-one R = H W =
2,3-dimethoxyphenyl R5 = hydrogen R6 = N-morpholino R7 = hydrogen
127 ##STR00062## 2-(2,3-dimethoxy- phenyl)-6-pyrrolidino-
quinolin-4-one R = H W = 2,3-dimethoxyphenyl R5 = hydrogen R6 =
N-pyrrolindino R7 = hydrogen 128 ##STR00063## 2-(2,5-dimethoxy-
phenyl)-6-morpholino- quinolin-4-one R = H W = 2,5-dimethoxyphenyl
R5 = hydrogen R6 = N-morpholino R7 = hydrogen 129 ##STR00064##
2-(2,5-dimethoxy- phenyl)-6-pyrrolidino- quinolin-4-one R = H W =
2,5-dimethoxyphenyl R5 = hydrogen R6 = N-pyrrolindino R7 = hydrogen
130 ##STR00065## 2-(2-methoxyphenyl)- 6-morpholino- quinolin-4-one
R = H W = 2-methoxyphenyl R5 = hydrogen R6 = N-morpholino R7 =
hydrogen 131 ##STR00066## 2-(2,5-dimethoxyphenyl)- 6-pyrrolidino-
quinolin-4-one R = H W = 2-methoxyphenyl R5 = hydrogen R6 =
N-pyrrolindino R7 = hydrogen 132 ##STR00067## 2-(4-methoxyphenyl)-
6-morpholinoquinolin- 4-one R = H W = 4-methoxyphenyl R5 = hydrogen
R6 = N-morpholino R7 = hydrogen 133 ##STR00068##
2-(4-methoxyphenyl)- 6-pyrrolidinoquinolin- 4-one R = H W =
4-methoxyphenyl R5 = hydrogen R6 = N-pyrrolindino R7 = hydrogen 134
##STR00069## 2-(2-Hydroxyphenyl)- 6-morpholinoquinolin- 4-one R = H
W = 2-hydroxyphenyl R5 = hydrogen R6 = N-morpholino R7 = hydrogen
135 ##STR00070## 2-(2-hydroxyphenyl)-- 6-pyrrolidinoquinolin- 4-one
R = H W = 2-hydroxyphenyl R5 = hydrogen R6 = N-pyrrolindino R7 =
hydrogen 136 ##STR00071## 2-(2-hydroxyphenyl)-
6-dimethylaminoquinolin- 4-one R = H W = 2-hydroxyphenyl R5 =
hydrogen R6 = N,N-dimethylamino R7 = hydrogen 137 ##STR00072##
2-(3-Hydroxyphenyl)- 6-morpholinoquinolin- 4-one R = H W =
3-hydroxyphenyl R5 = hydrogen R6 = N-morpholino R7 = hydrogen 138
##STR00073## 2-(3-hydroxyphenyl)- 6-pyrrolidinoquinolin- 4-one R =
H W = 3-hydroxyphenyl R5 = hydrogen R6 = N-pyrrolindino R7 =
hydrogen 139 ##STR00074## 2-(3-hydroxyphenyl)-
6-dimethylaminoquinolin- 4-one R = H W = 3-hydroxyphenyl R5 =
hydrogen R6 = N,N-dimethylamino R7 = hydrogen 140 ##STR00075##
2-(4-Hydroxyphenyl)- 6-morpholinoquinolin- 4-one R = H W =
4-hydroxyphenyl R5 = hydrogen R6 = N-morpholino R7 = hydrogen 141
##STR00076## 2-(4-hydroxyphenyl)- 6-pyrrolidinoquinolin- 4-one R =
H W = 4-hydroxyphenyl R5 = hydrogen R6 = N-pyrrolindino R7 =
hydrogen 142 ##STR00077## 2-(4-hydroxyphenyl)-
6-dimethylaminoquinolin- 4-one R = H W = 4-hydroxyphenyl R5 =
hydrogen R6 = N,N-dimethylamino R7 = hydrogen 143 ##STR00078##
2-(4-hydroxy-3- methoxyphenyl)- 6-morpholinoquinolin- 4-one R = H W
= 4-hydroxy- 3-methoxyphenyl R5 = hydrogen R6 = N-morpholino R7 =
hydrogen 143a ##STR00079## 2-(5-hydroxy-2- methoxyphenyl)-
6-morpholinoquinolin- 4-one R = H W = 5-hydroxy- 2-methoxyphenyl R5
= hydrogen R6 = N-morpholino R7 = hydrogen 143b ##STR00080##
2-(5-hydroxy-2-methoxy- phenyl)-6-pyrrolidino- quinolin-4-one R = H
W = 5-hydroxy-2- methoxyphenyl R5 = hydrogen R6 = N-pyrrolindino R7
= hydrogen 144 ##STR00081## 2-(4-hydroxy-3-methoxy-
phenyl)-6-pyrrolidino- quinolin-4-one R = H W = 4-hydroxy-3-
methoxyphenyl R5 = hydrogen R6 = N-pyrrolindino R7 = hydrogen 144a
##STR00082## 2-(2,5-dihydroxyphenyl)- 6-morpholinoquinolin- 4-one R
= H W = 2,5-dihydroxyphenyl R5 = hydrogen R6 = N-morpholino R7 =
hydrogen 144b ##STR00083## 2-(2,5-dihydroxy-phenyl)-
6-pyrrolidinoquinolin- 4-one R = H W = 2,5-dihydroxyphenyl R5 =
hydrogen R6 = N-pyrrolindino R7 = hydrogen 146 ##STR00084##
Dibenzyl 3-(4-oxo-6-(pyrrolidin- 1-yl)-1,4-dihydro
quinolin-2-yl)phenyl phosphate R = H W = 3-OR8-phenyl R5 = hydrogen
R6 = N-pyrrolindino R8 = P(.dbd.O)(O-benzyl)2 147 ##STR00085##
3-(4-Oxo-6-(pyrrolidin- 1-yl)-1,4-dihydro- quinolin-2-yl)phenyl
dihydrogen phosphate R = H W= 3-OR8-phenyl R5 = hydrogen R6 =
N-pyrrolindino R8 = P(.dbd.O)(OH)2 151 (JMC-39) ##STR00086##
2-(1-Naphthalenyl)- 6,7-methylenedioxy quinolin-4-one R = H W=
naphtha-1-yl R5 = hydrogen R6 and R7 = methylenedioxy 152
##STR00087## Dibenzyl 2-(1-naphthalenyl)-6,7-
methylenedioxyquinolin- 4-yl phosphate R = P(.dbd.O)(O-benzyl)2 W =
naphtha-1-yl R5 = hydrogen R6 and R7 = methylenedioxy 153
##STR00088## 2-(1-Naphthalenyl)- 6,7-methylenedioxy- quinolin-4-yl
dihydrogen phosphate R = P(.dbd.O)(OH)2 W = naphtha-1-yl R5 =
hydrogen R6 and R7 = methylenedioxy 156 (JMC-37) ##STR00089##
2-(3-Benzo[b]furyl)- 6,7-methylenedioxy- quinolin-4-one R = H W =
benzo[b] furan-3-yl R5 = hydrogen R6 and R7 = methylenedioxy 157
##STR00090## Dibenzyl 2-(3-benzo[b]furyl)- 6,7-methylenedioxy
quinolin-4-yl phosphate R = P(.dbd.O)(O-benzyl)2 W = benzo[b]
furan-3-yl R5 = hydrogen R6 and R7 = methylenedioxy 158
##STR00091## 2-(3-Benzo[b]furyl)- 6,7-methylenedioxy quinolin-4-yl
dihydrogen phosphate R = P(.dbd.O)(OH)2 W = benzo[b] furan-3-yl R5
= hydrogen R6 and R7 = methylenedioxy 166 ##STR00092##
2-(3-Hydroxy-5- methoxyphenyl)-6,7- methylenedioxyquinolin- 4-one R
= H W = 3-OR8-5- methoxyphenyl R5 = hydrogen R6 and R7 =
methylenedioxy 167 ##STR00093## Dibenzyl 2-(3-([bis-[(benzyl)
oxy]]phosphoryl)oxy- 5-methoxyphenyl)-6,7- methylenedioxyquinolin-
4-yl phosphate R = P(.dbd.O)(O-benzyl)2 W = 3-OR8-5- methoxyphenyl
R5 = hydrogen R6 and R7 = methylenedioxy R8 = P(.dbd.O)(O-benzyl)2
168 ##STR00094## 2-(3-([bis-[(benzyl) oxy]]phosphoryl)oxy-
5-methoxyphenyl)-6,7- methylenedioxyquinolin- 4-one R = H W =
3-OR8-5- methoxyphenyl R5 = hydrogen R6 and R7 = methylenedioxy R8
= P(.dbd.O)(O-benzyl)2 169 ##STR00095## 2-(3-(dihydrogen)
phosphate-5-methoxy- phenyl)-6,7-methylene- dioxyquinolin-4-one R =
H W = 3-OR8-5- methoxyphenyl R5 = hydrogen R6 and R7 =
methylenedioxy R8 = P(.dbd.O)(OH)2 JMC-1 ##STR00096## 2-(3-Benzo[b]
thienyl)-6,7-methylene- dioxyquinolin-4- one R = H W = benzo[b]
thiophen-3-yl R5 = hydrogen R6 and R7 = methylenedioxy JMC-36
##STR00097## 2-(2-Benzo[b]thienyl)-6,7- methylenedioxy-
quinolin-4-one R = H W = benzo[b] thiophen-2-yl R5 = hydrogen R6
and R7 = methylenedioxy JMC-38 ##STR00098## 2-(2-Benzo[b]furyl)-
6,7-methylenedioxy quinolin-4-one R = H W = benzo[b] furan-2-yl R6
and R7 = methylenedioxy R5 = H JMC-40 ##STR00099##
2-(2-Naphthalenyl)- 6,7-methylenedioxy quinolin-4-one R = H W =
naphtha-2-yl R5 = hydrogen R6 and R7 = methylenedioxy JMC-41
##STR00100## 2-(4-Quinolinyl)-6,7- methylenedioxy- quinolin-4-one R
= H W = quinolin-4-yl R5 = hydrogen R6 and R7 = methylenedioxy
JMC-42 ##STR00101## 2-(3-Quinolinyl)-6,7- methylenedioxy-
quinolin-4-one R = H W = quinolin-3-yl R5 = hydrogen R6 and R7 =
methylenedioxy
JMC-43 ##STR00102## 2-(2-Quinolinyl)-6,7- methylenedioxy-
quinolin-4-one R = H W = quinolin-2-yl R5 = hydrogen R6 and R7=
methylenedioxy JMC-44 ##STR00103## 2-(5-Quinolinyl)-6,7-
methylenedioxy- quinolin-4-one R = H W = quinolin-5-yl R5 =
hydrogen R6 and R7 = methylenedioxy JMC-45 ##STR00104##
2-(1-Anthracenyl)-6, 7-methylenedioxy- quinolin-4-one R = H W =
anthracen-1-yl R5 = hydrogen R6 and R7 = methylenedioxy
[0324] The foregoing description of the exemplary embodiments of
the invention has been presented only for the purposes of
illustration and description and is not intended to be exhaustive
or to limit the invention to the precise forms disclosed. The
embodiments and examples were chosen and described in order to
explain the principles of the invention and their practical
application so as to enable others skilled in the art to utilize
the invention and various embodiments and with various
modifications as are suited to the particular use contemplated.
Accordingly, the scope of the present invention is defined by the
appended claims rather than the foregoing description and the
exemplary embodiments described therein.
[0325] All references cited and discussed in this specification are
incorporated herein by reference in their entireties and to the
same extent as if each reference was individually incorporated by
reference.
* * * * *